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Water solubility

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Reference
Endpoint:
water solubility
Type of information:
experimental study
Adequacy of study:
key study
Study period:
June 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EU Method A.6 (Water Solubility)
Principles of method if other than guideline:
Previous feasibility work provided indicative saturation levels for the test item (approximately 320 mg/l) and, as a result, the preliminary test detailed in Method A6 was not performed.
GLP compliance:
yes (incl. QA statement)
Type of method:
flask method
Water solubility:
167 mg/L
Temp.:
25 °C
pH:
3.11
Details on results:
The results obtained indicated increasing water solubility over time and as a result the mean value of tests 3 (Day 3), 4 (Day 4) and 5 (Day 5) was therefore used to calculate the mean water solubility value. The results were comparable to the light control sample and the results of tests 1 (Day 1) and 2 (Day 2) were significantly lower and hence not used. The tests for Day 3, 4 and 5 were within the acceptance criteria of the guideline (<15%).

Results of pH analysis

 Test solution  pH Lambda max (nm)   Absorbance  Amount determined from linearity graph (mg/L) Water solubility (mg/L in filtrate) 
 H2O in DMSO 7.33 No peaks detected     Not Applicable  Not Applicable
1 day test 3.34 352.8 0.266 5.43 136
 2 day test 3.28 352.9 0.254 5.18 130
 3 day test 3.28 352.9 0.332 6.78 170
 4 day test 3.16 352.7 0.323 6.60 165
 5 day test 3.11 352.6 0.324 6.62 166
 Light control test 3.08 352.6 0.325 6.64 166

Analysis of Water Solubility Test Solutions by Mass Spectrometry

The water solubility test solutions were analysed byFlow Injection Electrospray Mass Spectrometry after intial examination by Direct Infusion.

  

Analysis Parameters

All water solubility test solutions were submitted for analysis, without any additional treatment, initially by flow injection electrospray in positive and negative ion detection modes using the conditions detailed below. A blank control (water) was analysed in the same manner.

 

Day 3, 4, 5 and Light Control test solutions were analysed by positive ion detection mode on the same day as UV analysis, but were then stored in a refrigerator for 12 days until being analysed by negative ion detection mode.

 

Day 1 and 2 test solutions were analysed by negative ion detection mode after storage for 4 days in a refrigerator but were then stored in a refrigerator for a further 7 days until being analysed by positive ion detection mode.

 

On removal from the refrigerator after 12 days storage it was observed that a white precipitate had settled out of solution in test solutions from Day 3, 4, 5 and light control. No precipitate was observed in the Day 1 and 2 test solutions. As a result, the overlying solution was removed for analysis of the Day 3, 4, 5 and light control test solutions.

 

Initial examination by direct infusion gave spectra that contained numerous ions which were also present in the data from the water control and therefore these data are not reported. In order to generate more useful spectra the test solutions were examined by flow injection electrospray MS so that the background spectra could be subtracted from the sample data. The flow injection electrospray analysis was performed on all test solutions after storage in the refrigerator for 11 or 12 days as detailed above.

 

Results

No evidence of the test item was observed in positive ion mode. All of the positive ion spectra showed the following ions:

 

m/z129, 173, 217, 261 etc. to 569, consistent with [M+Na]+ from polyethylene glycol (i.e. H[OC2H4]nOH where n= 2 to 12), andm/z331, 375, 419, 463 etc. to 947, consistent with [M+Na]+from polyethoxylated nonylphenol (i.e. C9H19-Ph-O[C2H4O]nH where n= 2 to 16).

 

Comparison of the ion intensities suggests that the ethoxylated nonylphenol components were present at relatively higher levels in the day 1 and 2 samples and the polyethylene glycol components were dominant in the day 3 to 5 samples. It is not known why the intensity of the ethoxylated nonyl phenol and the polyethylene glycol varied over time.

 

Polyethoxylated species ionise well in positive ion mode and may suppress ionisation of other species present (Antignacet al., 2005). As a result, the test substance may not be detected when polyethoxylated species are present. It is not clear why the ethoxylated species interferes in this experiment and not in the preceding feasibility study.

 

The negative ion spectra from all the solutions showed an ion atm/z149, likely due to [M]-that results from the fragmentation of the dimer test item, due to the reducing conditions present in negative ion mass spectroscopy.

 

The ions atm/z117 is likely due to the dihydroxy equivalent of the dithio monomer fragment. The ions at 58 and 90 are unidentified fragments.

 

Conclusion

On review of the mass spectrometry data obtained from the water solubility test solutions, no evidence of the test item was observed in positive ion mode.

 

In negative ion mode an ion at m/z 149 observed, consistent with the [M]-of the monomer fragment expected from the cleavage of the disulphide bond of the test item.

 

Mass spectrometry cannot differentiate between the various tautomers (of either the test item or the monomer fragment); tautomers, by definition, have equal mass. UV-Vis method may or may not differentiate between the tautomers, but for the purposes of this analysis, this report assumes that the UV absorbance reflects the total of all three tautomers of the test substance as well as the conjugate bases present in aqueous solution.

Conclusions:
Interpretation of results (migrated information): moderately soluble (100-1000 mg/L)
The reported water solubility result is 167 mg/L at 25 +/- 1°C.
Executive summary:

According to EU method A.6 the water solubility of 5,5'-Dithiodi-1,3,4-thiadiazole-2(3H)-thione is 167 mg/L at 25°C.

Description of key information

Key value for chemical safety assessment

Water solubility:
167 mg/L
at the temperature of:
25 °C

Additional information

Key Study:

In an EU Method A.6 (shake flask) study, conducted according to GLP, the water solubility of 5,5'-Dithiodi-1,3,4-thiadiazole-2(3H)-thione is 167 mg/L at 25°C ± 1°C (Intertek Pharmaceutical Services Manchester, 2016).