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EC number: 418-570-8 | CAS number: 25383-07-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- 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
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- 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
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- September 4, 1994 - September 23, 1994
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 995
- Report date:
- 1995
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
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- (R)-α-phenylethylammonium (-)-(1R, 2S)-(1,2-epoxypropyl)phosphonate monohydrate
- EC Number:
- 418-570-8
- EC Name:
- (R)-α-phenylethylammonium (-)-(1R, 2S)-(1,2-epoxypropyl)phosphonate monohydrate
- Cas Number:
- 25383-07-7
- Molecular formula:
- C11H20NO5P
- IUPAC Name:
- (R)-α-phenylethylammonium (-)-(1R, 2S)-(1,2-epoxypropyl)phosphonate monohydrate
- Details on test material:
- - Name of test material (as cited in study report): Fosfomycin PEA salt
- Physical state: white crystalline powder
- Lot/batch No.: 4177
- Expiration date of the lot/batch: at least 3 years from manufacturing date
- Storage condition of test material: at room temperature protected from light
- Other: June 10, 1994
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:
- other: TA 1535, 1537, 102, 98 ant 100: Defect in the histidine gene (His-), a deep rough (rfa) character and an uvrB deletion (uvrB-). TA98, 100 and 102: ampicillin resistant. TA102 tetracycline resistant.
- Metabolic activation:
- with and without
- Metabolic activation system:
- S9 Mix
- Test concentrations with justification for top dose:
- Test 1: 50, 150, 500, 1500 and 5000 µg/plate (with and without metabolic activation)
Test 2: 1.5, 5, 15, 50 and 150 µg/plate (with metabolic activation) and 5, 15, 50, 150 and 500 µg/plate (without metabolic activation)
Test 3 (repetition of test 2) - Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: [water for injection]
- Justification for choice of solvent/vehicle: suitable solvent for the test article
Controlsopen allclose all
- Negative solvent / vehicle controls:
- yes
- Remarks:
- Water for injection
- Positive controls:
- yes
- Positive control substance:
- other: Hydrazine sulphate (Hyd)
- Remarks:
- S. typhimurium TA 1535, without metabolic activation (direct test)
- Positive controls:
- yes
- Positive control substance:
- 9-aminoacridine
- Remarks:
- S. typhimurium TA 1537, without metabolic activation (direct test) Migrated to IUCLID6: 9-aminoacridine HCL monohydrate (9-AA)
- Positive controls:
- yes
- Positive control substance:
- mitomycin C
- Remarks:
- S. typhimurium TA 102, without metabolic activation (direct test) Migrated to IUCLID6: (Mito)
- Positive controls:
- yes
- Positive control substance:
- other: Doxorubicine HCl (Doxo)
- Remarks:
- S. typhimurium TA 98 and 100, without metabolic activation (direct test)
- Positive controls:
- yes
- Positive control substance:
- other: 2-aminofluorene (2-AF)
- Remarks:
- S. typhimurium TA 98, 100 and 102, with metabolic activation (indirect test)
- Details on test system and experimental conditions:
- METHOD OF APPLICATION:
TEST 1): in agar (plate incorporation)
0.1 ml of the test article or negative or positive control solutions was put into sterile test tubes containing 2.5 ml (test without) or 2 ml (test with) of soft agar kept liquid in a thermostatic bath at 45 ºC. A suspension of Salmonella strains in a stationary growth phase (0.1 ml) was rapidly added. For the test with metabolic activation 0.5 ml of S9 Mix was also added. The test tubes were shaken rapidly and the contents poured onto plates containing solid selective growth medium. The plates were incubated at 37 ºC for 72 hours.
Repetition of the assay: The experiment was repeated in an independent assay. Since negative results were obtained with metabolic activation in the first trial, the repeat test followed the pre-incubation method.
TEST 2): preincubation
0.5 ml of S9 Mix (test with metabolic activation) were dispensed in sterile test tubes placed in an ise bath. 0.1 ml of bacterial suspension and 0.1 ml of the test or control article solutions according to the dosage levels, were introduced. The test tubes were gently vortexed and incubated at 37 ºC for 20 min, in a horizontally shaking thermostatic bath. At the end of incubation, 2 ml of soft agar (kept liquid in a thermostatic bath at about 45 ºC were added to each tube. The test tubes were rapidly shaken and the contents poured onto plates containing solid selected growth medium. The plates were incubated at 37 ºC for 72 hours.
TEST 3): A third experiment was carried out in order to confirm the results obtained in the second one.
DURATION
- Preincubation period: 20 min at tests 2 and 3, preincubation tests.
- Exposure duration: 72 h at tests 1, 2 and 3.
NUMBER OF REPLICATIONS: 3 plates per dose at tests 1, 2 and 3.
OTHER:
NEGATIVE AND POSITIVE CONTROL DOSAGE LEVELS:
Negative control: water for injection, 100 µg/plate.
Positive controls without metabolic activation (direct test):
S. typhimurium TA 1535: Hydrazine sulphate (Hyd): 500 µg/plate (solution: 5 mg/ml in water)
S. typhimurium TA 1537:9-amioacridine HCL monohydrate (9-AA): 40 µg/plate (solution: 0.4 mg/ml in DMSO)
S. typhimurium TA 102: Mitomycin C (Mito): 0.5 µg/plate (solution: 0.005 mg/ml in water)
S. typhimurium TA 98 and 100: Doxorubicine HCL (Doxo): 4 µg/plate (solution: 0.04 mg/ml in DMSO)
Positive controls with metabolic activation (indirect test):
S. typhimurium TA 98, 100 and 102: 2-aminofluorene (2-AF): 5 µg/plate (solution: 0.05 mg/ml in water)
PREPARATION OF S9 MIX:
S9 fraction (9000 g supernatant) was prepared from adult male Sprague Dawley rats pretreated by intraperitoneal route at 500 mg/kg (2.5 mg/kg) with Aroclor 1254 (Alltech). S9 Mix consisted of S9 plus cofactors. - Evaluation criteria:
- The test article is considered to have elicitated a positive response when:
- The number of reverted colonies is significantly higher when compared with the number of revertants in the solvent controls (as determined by Student's t);
AND
- Either: a dose-response con be verified, that is, a positive correlation between the number of revertants and the dose in an interval of at least 3 doses (linear regression test);
- Or: a statistically significant increase is recorded at one dose only, when confirmed in independent assays. - Statistics:
- The mean and standard deviation was calculated for reversions read in each dosage group.
Comparison of the spontaneous reversions (in the negative control) with the ones in the test article plates and ini the positive control plates was done by student's t test.
Dose-effect linear regression was done if statistically significant differences were found.
Results and discussion
Test resultsopen allclose all
- Key result
- 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:
- cytotoxicity
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- 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:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- ADDITIONAL INFORMATION ON CYTOTOXICITY: At dosage levels of 1500 and 5000 µg/plate, both in the presence and in the absence of metabolic activation and 500 µg/plate with metabolic activation.
Any other information on results incl. tables
Table 1. Mutagenicity test with S. typhimurium strain TA 1535 without metabolic activation.
Compound |
Concentration (µg/p) |
Reversions/plate |
Mean |
SD |
||
Test 1 |
||||||
Control |
- |
29 |
27 |
24 |
26.67 |
2.52 |
Test article |
50 |
25 |
21 |
28 |
24.67 |
3.51 |
150 |
23 |
20 |
20 |
21.00 |
1.73 |
|
500 |
19 |
17 |
19 |
18.33 |
1.15 |
|
1500 |
Toxic |
- |
|
|||
5000 |
Toxic |
- |
|
|||
Hydrazine |
500 |
103 |
127 |
131 |
120.33* |
15.14 |
Test 2 |
||||||
Control |
- |
27 |
29 |
24 |
26.67 |
2.52 |
Test article |
5 |
27 |
27 |
21 |
25.00 |
3.46 |
15 |
29 |
25 |
24 |
26.00 |
2.65 |
|
50 |
21 |
26 |
27 |
24.67 |
3.21 |
|
150 |
24 |
22 |
25 |
23.67 |
1.53 |
|
500 |
12 |
17 |
14 |
14.33 |
2.52 |
|
Hydrazine |
500 |
116 |
106 |
121 |
114.33* |
7.64 |
Test 3 |
||||||
Control |
- |
23 |
21 |
28 |
24.00 |
3.61 |
Test article |
5 |
24 |
26 |
21 |
23.67 |
2.52 |
15 |
23 |
23 |
22 |
22.67 |
0.58 |
|
50 |
27 |
21 |
20 |
22.67 |
3.79 |
|
150 |
23 |
23 |
24 |
23.33 |
0.58 |
|
500 |
19 |
16 |
20 |
18.33 |
2.08 |
|
Hydrazine |
500 |
106 |
127 |
117 |
116.67* |
10.50 |
*p < 0.001
Table 2. Mutagenicity test with S. typhimurium strain TA 1537 without metabolic activation.
Compound |
Concentration (µg/p) |
Reversions/plate |
Mean |
SD |
||
Test 1 |
||||||
Control |
- |
12 |
10 |
13 |
11.67 |
1.53 |
Test article |
50 |
8 |
7 |
10 |
8.33 |
1.53 |
150 |
13 |
7 |
12 |
10.67 |
3.21 |
|
500 |
13 |
11 |
9 |
11.0 |
2.00 |
|
1500 |
2 |
3 |
5 |
3.33 |
1.53 |
|
5000 |
Toxic |
- |
|
|||
9-AA |
40 |
40 |
57 |
44 |
47.00* |
8.89 |
Test 2 |
||||||
Control |
- |
12 |
7 |
15 |
11.33 |
4.04 |
Test article |
5 |
9 |
6 |
13 |
9.33 |
3.51 |
15 |
7 |
14 |
11 |
10.67 |
3.51 |
|
50 |
11 |
12 |
8 |
10.33 |
2.08 |
|
150 |
13 |
10 |
8 |
10.33 |
2.52 |
|
500 |
10 |
5 |
9 |
8.00 |
2.65 |
|
9-AA |
40 |
56 |
47 |
59 |
54.00* |
6.24 |
Test 3 |
||||||
Control |
- |
10 |
9 |
9 |
9.33 |
0.58 |
Test article |
5 |
13 |
9 |
7 |
9.67 |
3.06 |
15 |
4 |
11 |
9 |
8.00 |
3.61 |
|
50 |
8 |
10 |
3 |
7.00 |
3.61 |
|
150 |
8 |
9 |
10 |
9.00 |
1.00 |
|
500 |
5 |
7 |
3 |
5.00 |
2.00 |
|
9-AA |
40 |
49 |
55 |
58 |
54.00* |
4.58 |
*p < 0.001
Table 3. Mutagenicity test with S. typhimurium strain TA 102 without metabolic activation.
Compound |
Concentration (µg/p) |
Reversions/plate |
Mean |
SD |
||
Control |
- |
272 |
322 |
292 |
295.33 |
25.17 |
Test article |
50 |
268 |
316 |
300 |
294.67 |
24.44 |
150 |
304 |
248 |
265 |
272.33 |
28.71 |
|
500 |
166 |
130 |
148 |
148.00 |
18.00 |
|
1500 |
Toxic |
- |
|
|||
5000 |
Toxic |
- |
|
|||
2-Nitrofluorene |
2.5 |
940 |
869 |
918 |
909.0* |
36.35 |
Test 2 |
||||||
Control |
- |
290 |
311 |
271 |
290.67 |
20.01 |
Test article |
5 |
271 |
284 |
260 |
271.67 |
12.01 |
15 |
305 |
290 |
271 |
28..67 |
17.04 |
|
50 |
280 |
310 |
265 |
285.00 |
22.91 |
|
150 |
280 |
320 |
278 |
292.67 |
23.69 |
|
500 |
240 |
256 |
211 |
235.67 |
22.81 |
|
2-Nitrofluorene |
2.5 |
980 |
1040 |
1020 |
1013.33* |
30.55 |
Test 3 |
||||||
Control |
- |
254 |
308 |
320 |
294.00 |
35.16 |
Test article |
5 |
328 |
306 |
296 |
310.00 |
16.37 |
15 |
309 |
260 |
272 |
280.33 |
25.54 |
|
50 |
322 |
280 |
320 |
307.33 |
23.69 |
|
150 |
252 |
260 |
260 |
257.33 |
4.62 |
|
500 |
212 |
201 |
218 |
210.33 |
8.62 |
|
2-Nitrofluorene |
2.5 |
900 |
1020 |
940 |
953.33* |
61.10 |
*p < 0.001
Table 4. Mutagenicity test with S. typhimurium strain TA 98 without metabolic activation.
Compound |
Concentration (µg/p) |
Reversions/plate |
Mean |
SD |
||
Control |
- |
48 |
37 |
45 |
43.33 |
5.69 |
Test article |
50 |
44 |
40 |
45 |
43.00 |
2.65 |
150 |
48 |
41 |
43 |
44.0 |
3.61 |
|
500 |
30 |
32 |
26 |
29.33 |
3.06 |
|
1500 |
12 |
7 |
7 |
8.67 |
2.89 |
|
5000 |
Toxic |
- |
|
|||
Doxorubicine |
4 |
1020 |
980 |
1000 |
1000.00* |
20.00 |
Test 2 |
||||||
Control |
- |
47 |
38 |
41 |
42.00 |
4.58 |
Test article |
5 |
37 |
43 |
43 |
41.00 |
3.46 |
15 |
42 |
44 |
41 |
42.33 |
1.53 |
|
50 |
45 |
43 |
35 |
41.00 |
5.29 |
|
150 |
39 |
41 |
43 |
41.00 |
2.00 |
|
500 |
25 |
30 |
37 |
30.67 |
6.03 |
|
Doxorubicine |
4 |
846 |
828 |
864 |
846.00* |
18.00 |
Test 3 |
||||||
Control |
- |
32 |
42 |
36 |
36.67 |
5.03 |
Test article |
5 |
36 |
38 |
25 |
33.00 |
7.00 |
15 |
37 |
29 |
33 |
33.00 |
4.00 |
|
50 |
31 |
28 |
26 |
38.33 |
2.52 |
|
150 |
25 |
37 |
26 |
29.33 |
6.66 |
|
500 |
33 |
27 |
31 |
30.33 |
3.06 |
|
Doxorubicine |
4 |
804 |
888 |
824 |
850.67* |
333.31 |
*p < 0.001
Table 5. Mutagenicity test with S. typhimurium strain TA 100 without metabolic activation.
Compound |
Concentration (µg/p) |
Reversions/plate |
Mean |
SD |
||
Control |
- |
204 |
180 |
201 |
195.00 |
13.08 |
Test article |
50 |
195 |
186 |
183 |
188.00 |
6.24 |
150 |
179 |
190 |
185 |
184.67 |
5.51 |
|
500 |
130 |
160 |
140 |
143.33 |
15.28 |
|
1500 |
Toxic |
- |
|
|||
5000 |
Toxic |
- |
|
|||
Doxorubicine |
4 |
560 |
544 |
550 |
551.33* |
8.08 |
Test 2 |
||||||
Control |
- |
195 |
180 |
171 |
182.00 |
12.12 |
Test article |
5 |
188 |
166 |
193 |
182.33 |
14.36 |
15 |
180 |
170 |
180 |
176.67 |
5.77 |
|
50 |
203 |
174 |
182 |
186.33 |
14.98 |
|
150 |
186 |
190 |
188 |
188.00 |
2.00 |
|
500 |
165 |
140 |
151 |
152.00 |
12.53 |
|
Doxorubicine |
4 |
495 |
510 |
530 |
511.67* |
17.56 |
Test 3 |
||||||
Control |
- |
206 |
204 |
212 |
207.33 |
4.16 |
Test article |
5 |
200 |
206 |
195 |
200.33 |
5.51 |
15 |
180 |
172 |
208 |
186.67 |
18.90 |
|
50 |
200 |
196 |
210 |
202.00 |
7.21 |
|
150 |
204 |
202 |
184 |
196.67 |
11.02 |
|
500 |
176 |
197 |
198 |
190.33 |
12.42 |
|
Doxorubicine |
4 |
572 |
652 |
570 |
598.00* |
46.78 |
*p < 0.001
Table 6. Mutagenicity test with S. typhimurium strain TA 1535 with metabolic activation.
Compound |
Concentration (µg/p) |
Reversions/plate |
Mean |
SD |
||
Control |
- |
24 |
30 |
27 |
27.00 |
3.00 |
Test article |
50 |
28 |
24 |
25 |
25.67 |
2.08 |
150 |
26 |
26 |
27 |
26.33 |
0.58 |
|
500 |
Toxic |
- |
|
|||
1500 |
Toxic |
- |
|
|||
5000 |
Toxic |
- |
|
|||
Test 2 |
||||||
Control |
- |
23 |
22 |
28 |
24.33 |
3.21 |
Test article |
1.5 |
23 |
17 |
23 |
21.00 |
3.46 |
5 |
22 |
22 |
25 |
23.00 |
1.73 |
|
15 |
24 |
23 |
26 |
24.33 |
1.53 |
|
50 |
19 |
27 |
18 |
21.33 |
4.93 |
|
150 |
21 |
16 |
19 |
18.67 |
2.52 |
|
Test 3 |
||||||
Control |
- |
21 |
25 |
27 |
24.33 |
3.06 |
Test article |
1.5 |
23 |
18 |
20 |
20.33 |
2.52 |
5 |
15 |
19 |
19 |
17.67 |
2.31 |
|
15 |
27 |
18 |
23 |
22.67 |
4.51 |
|
50 |
18 |
17 |
22 |
19.00 |
2.65 |
|
150 |
18 |
17 |
19 |
18.00 |
1.00 |
Table 7. Mutagenicity test with S. typhimurium strain TA 1537 with metabolic activation.
Compound |
Concentration (µg/p) |
Reversions/plate |
Mean |
SD |
||
Control |
- |
12 |
15 |
12 |
13.00 |
1.73 |
Test article |
50 |
7 |
12 |
5 |
8.00 |
3.61 |
150 |
7 |
8 |
6 |
7.00 |
1.00 |
|
500 |
2 |
3 |
3 |
2.67 |
0.58 |
|
1500 |
Toxic |
- |
|
|||
5000 |
Toxic |
- |
|
|||
Test 2 |
||||||
Control |
- |
12 |
10 |
12 |
11.33 |
1.15 |
Test article |
1.5 |
10 |
11 |
12 |
11.00 |
1.00 |
5 |
13 |
14 |
8 |
11.67 |
3.21 |
|
15 |
13 |
11 |
12 |
12.00 |
1.00 |
|
50 |
8 |
13 |
9 |
10.00 |
2.65 |
|
150 |
8 |
6 |
9 |
7.67 |
1.53 |
|
Test 3 |
||||||
Control |
- |
10 |
11 |
11 |
10.67 |
0.58 |
Test article |
1.5 |
11 |
10 |
8 |
9.67 |
1.53 |
|
5 |
12 |
6 |
9 |
9.00 |
3.00 |
|
15 |
11 |
12 |
10 |
11.00 |
1.00 |
|
50 |
9 |
10 |
8 |
9.00 |
1.00 |
|
150 |
8 |
8 |
6 |
7.33 |
1.15 |
Table 8. Mutagenicity test with S. typhimurium strain TA 102 with metabolic activation.
Compound |
Concentration (µg/p) |
Reversions/plate |
Mean |
SD |
||
Control |
- |
252 |
315 |
317 |
294.67 |
36.96 |
Test article |
50 |
294 |
270 |
280 |
281.33 |
12.06 |
150 |
307 |
260 |
268 |
278.33 |
25.15 |
|
500 |
200 |
164 |
170 |
178.00 |
19.29 |
|
1500 |
Toxic |
- |
|
|||
5000 |
Toxic |
- |
|
|||
2-AF |
5 |
976 |
1012 |
988 |
992.00* |
18.33 |
Test 3 |
||||||
Control |
- |
304 |
318 |
316 |
312.67 |
7.57 |
Test article |
1.5 |
300 |
272 |
308 |
293.33 |
18.90 |
|
5 |
300 |
302 |
286 |
296.00 |
8.72 |
|
15 |
280 |
277 |
308 |
288.33 |
17.10 |
|
50 |
309 |
310 |
279 |
299.33 |
17.62 |
|
150 |
282 |
263 |
255 |
266.67 |
13.87 |
2-AF |
5 |
1200 |
940 |
1120 |
1086.67* |
133.17 |
*p < 0.001
Table 9. Mutagenicity test with S. typhimurium strain TA 98 with metabolic activation.
Compound |
Concentration (µg/p) |
Reversions/plate |
Mean |
SD |
||
Control |
- |
48 |
47 |
51 |
48.67 |
2.08 |
Test article |
50 |
48 |
53 |
44 |
48.33 |
4.51 |
150 |
31 |
36 |
39 |
35.33 |
4.04 |
|
500 |
Toxic |
- |
|
|||
1500 |
Toxic |
- |
|
|||
5000 |
Toxic |
- |
|
|||
2-AF |
5 |
1128 |
1164 |
1112 |
1134.67* |
26.67 |
Test 2 |
||||||
Control |
- |
52 |
44 |
46 |
47.33 |
4.16 |
Test article |
1.5 |
48 |
40 |
50 |
46.00 |
5.29 |
5 |
41 |
49 |
47 |
45.67 |
4.16 |
|
15 |
46 |
46 |
52 |
48.00 |
3.46 |
|
50 |
51 |
44 |
47 |
47.33 |
3.51 |
|
150 |
40 |
33 |
36 |
36.33 |
3.51 |
|
2-AF |
5 |
1200 |
1140 |
1170 |
1170.00* |
30.00 |
Test 3 |
||||||
Control |
- |
45 |
41 |
43 |
46.33 |
4.16 |
Test article |
1.5 |
39 |
45 |
43 |
42.33 |
3.06 |
|
5 |
41 |
45 |
67 |
51.00 |
14.00 |
|
15 |
39 |
31 |
40 |
36.67 |
4.93 |
|
50 |
39 |
40 |
50 |
43.00 |
6.08 |
|
150 |
35 |
46 |
38 |
39.67 |
5.69 |
2-AF |
5 |
1450 |
1400 |
1466 |
1438.67* |
34.43 |
*p < 0.001
Table 10. Mutagenicity test with S. typhimurium strain TA 100 with metabolic activation.
Compound |
Concentration (µg/p) |
Reversions/plate |
Mean |
SD |
||
Control |
- |
186 |
226 |
211 |
207.67 |
20.21 |
Test article |
50 |
162 |
184 |
184 |
176.67 |
12.70 |
150 |
190 |
200 |
180 |
190.00 |
10.00 |
|
500 |
30 |
48 |
72 |
50.00 |
21.07 |
|
1500 |
Toxic |
- |
|
|||
5000 |
Toxic |
- |
|
|||
2-AF |
5 |
820 |
810 |
900 |
843.33* |
49.33 |
Test 2 |
||||||
Control |
- |
203 |
195 |
207 |
201.67 |
6.11 |
Test article |
1.5 |
188 |
200 |
176 |
188.00 |
12.00 |
|
5 |
195 |
196 |
171 |
187.33 |
14.15 |
|
15 |
206 |
180 |
194 |
193.33 |
13.01 |
|
50 |
181 |
177 |
185 |
181.00 |
4.00 |
|
150 |
194 |
160 |
175 |
176.33 |
17.04 |
2-AF |
5 |
940 |
875 |
900 |
905.00* |
32.79 |
Test 3 |
||||||
Control |
- |
193 |
185 |
195 |
191.00 |
5.29 |
Test article |
1.5 |
207 |
191 |
195 |
197.67 |
8.33 |
|
5 |
189 |
195 |
206 |
196.67 |
8.62 |
|
15 |
176 |
208 |
1778 |
187.33 |
17.93 |
|
50 |
200 |
184 |
173 |
185.67 |
13.58 |
|
150 |
173 |
174 |
169 |
172.00 |
2.65 |
2-AF |
5 |
940 |
880 |
910 |
910.00 |
30.00 |
*p < 0.001
Applicant's summary and conclusion
- Conclusions:
- The test article Fosfomycin PEA salt did not induce any significant increase in the number of reversions up to the concentrations of 150 and 500 µg/plate in the presence and in the absence of metabolic activation, respectively, in TA 1535, TA 1537, TA 102, TA 98 and TA100 Salmonella typhimurium strains, in two independent experiments.
- Executive summary:
The mutagenic potency of Fosfomycin PEA salt was investigate using Salmonella typhimurium TA 1535, TA 1537, TA 102, TA 98 and TA 100 as tester strains. The study was performed using the plate incorporation assay with and without liver homologate (S9 Mix). Three independent experiments were performed, setting up triplicate plates for each experimental point. Hydrazine sulphate, 9-aminoacridine HCl monohydrate, Mitomycin C, Doxorubicine HCl and 2-aminofluorene served as positive controls to test the mutagenicity of the bacterial strains as well as the activity of the metabolizing system. The negative control was the test article solvent, water for injection. In the first experiment, the test article proved to be severely cytotoxic on the test system at the dosage levels of 1500 and 5000 µg/plate, both in the presence and in the absence of metabolic and 500 µg/plate with metabolic activation.
At these dosages, in fact, a complete absence or a strong decrease in the background lawn and in the number of revertant colonies in comparison with the negative control was observed. At 150 and 500 µg/plate with and without metabolic activation, respectively, a slight reduction in the background lawn was detected. The Ames test was therefore repeated assaying test article dosages in the range of concentrations 0.15-150 µg/plate in the trial with metabolic activation and 5-500 µg/plate in the trial without metabolic activation. Then a third experiment was carried out in order to confirm the results obtained in the second one. In the concentrations rages investigated, the test substance did not show any mutagenic activity with or without the addition of S9 liver homogenate fractions. The known reversion properties were determined for the tester strains with the control substances; the positive responses confirmed the good metabolic activity of the liver homogenate fractions.
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