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Water solubility

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Endpoint:
water solubility
Type of information:
experimental study
Adequacy of study:
key study
Study period:
September 2002 - October 2002
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study conducted following OECD guidline.
Qualifier:
according to
Guideline:
OECD Guideline 105 (Water Solubility)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Type of method:
flask method
Water solubility:
32 mg/L
Temp.:
20 °C
pH:
>= 5.9 - <= 7
Details on results:
-Preliminary test:
The preliminary estimate of water solubility was 8.41E-2 g/l.

-Definitive test:
The concentration (g/l) of test material in the sample solutions is shown in Table 2.

Three peaks were observed in the chromatograms for the test material. The first two peaks (~3.9 and 4.1 minutes) account for approximately 90% of the total peak area and are therefore assumed to be due to the two isomers of the test material. The third peak (~5.7 minutes) is assumed to be an impurtiy and therefore not included in the calculated results. The change in profile betweem the standard and sample chromatograms indicates that one isomer of the test material is more soluble than the others.

Table 2

 

Sample number

Time Shaken at ~30 deg C (hours)

Time equilibiated at 20 deg C (hours)

concentration (g/l)

Solution pH

1

24

24

3.27E-02

6.4

2

48

24

2.74E-02

5.9

3

72

24

3.56E-02

7.0

 

Mean concentration: 3.20E-2 g/l at 20.0 +/- 0.5 deg C

Range: 2.74E-2 to 3.56E-2 g/l

Conclusions:
Interpretation of results (migrated information): slightly soluble (0.1-100 mg/L)
The water solubility ofZMB2 has been determined to be 32 mg/L of solution at 20 +/- 0.5 deg C.
Endpoint:
water solubility
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1990-05-07 - 1990-06-26
Qualifier:
no guideline available
GLP compliance:
yes
Water solubility:
72.61 mg/L
Conc. based on:
other: MB2 (dissolved fraction)
Water solubility:
1.33 mg/L
Conc. based on:
other: zinc (dissolved fraction)
Details on results:
Measured mean concentrations in water solubility study:
72.61 mg/L MB2
1.33 mg/L Zn2+
From these concentrations the following measured molar ratio results:
0.4421 : 0.0203
= 1 : 0.046
Theoretical molar ratio:
2 : 1
= 1 : 0.5

In aqueous solution of ZMB2 at pH 7, ZMB2 is dissolved as MB2 and Zn2+. The dissolved Zn2+ mainly precipitates as Zn(OH)2. Only approximately 9% (0.046/0.5 = 0.09) of the theoretically expected Zn2+ concentration is dissolved in the aqueous phase. In other words, for >90% of the MB2 molecules there is no stoichiometric Zn2+ counterpart in solution. The dissolved MB2 part was about 22 times higher than the Zn2+ part while a theoretical ratio of 2:1 is expected.

This water solubility study demonstrates that ZMB2 is splitting into zinc ions and MB2 rather than being present in undissociated form in aqueous solution. For the dissolved fraction of zinc, formally there is no information available from this study if this is bound to MB2 molecules in solution or dissolved in water as zinc ion. However, from weight of evidence presented in this document, the dissolved fraction of zinc must clearly be assigned to ionic Zn2+ in solution and not to undissociated ZMB2 dissolved as a whole molecule.

The statement in the study report that “Vulkanox ZMB2/C5 is not stoichiometrically soluble in water” could more accurately be worded as follows: “Vulkanox ZMB2 dissolves in a stoichiometric ratio, but the zinc does not remain in solution.” This means that zinc concentration is not useful as a measurement of ZMB2 concentration in aqueous environments.

Conclusions:
The measured mean concentrations in water solubility study are as follows:
72.61 mg/L (MB2)
1.33 mg/L (Zn2+)
In aqueous solution of ZMB2 at pH 7, ZMB2 is dissolved as MB2 and Zn2+. The dissolved Zn2+ mainly precipitates as Zn(OH)2. Only approximately 9% of the theoretically expected Zn2+ concentration is dissolved in the aqueous phase.

Description of key information

Key Study:

Water Solubility = 32 mg/L (20 °C); OECD 105; Safepharm (2002)

Supporting Study:

Water Solubility = 72.61 mg/L (MB2), 1.33 mg/L (Zn2+); No guideline followed; Bayer (1990)

Key value for chemical safety assessment

Water solubility:
32 mg/L
at the temperature of:
20 °C

Additional information

When considering the results of the investigations carried out to support the read-across from 1,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione (MB2) to 2H-Benzimidazole-2-thione, 1,3-dihydro-4(or 5)-methyl-, zinc salt (2:1) (ZMB2) (LANXESS, 2018), the results of water solubility studies conducted with this substance must be reconsidered in light of new information.  The overall conclusion in LANXESS (2018) is that ZMB2 exhibits its salt characteristic in aqueous solution, i.e., dissolving in water to MB2 and zinc ions in a matter of seconds.  For full details of the investigations conducted, refer to Section 13.2 of IUCLID.

Water Solubility Study (GLP, SafePharm, 2002) - Key Study

This is the key study used for the water solubility endpoint as it is the newest study with a more detailed study report compared to older studies.  In this study three peaks were observed in the chromatograms for the test item. The first two peaks (~3.9 and 4.1 minutes) account for approximately 90% of the total peak area and were assumed to represent the two isomers of the test item (ZMB2). The third peak (~5.7 minutes) was assumed to be an impurity and therefore not included in the calculated results. The change in profile between the standard and sample chromatograms indicated that one isomer of the test material is more soluble than the others.

When applying the method used for LANXESS (2018), the two MB2 isomers elute at 5.63 and 5.88 minutes, i.e. a difference in retention time of approx. 0.2 minutes (0.25 minutes, which fits well with the results of this study considering the higher retention time of the LANXESS method).

From sample treatment (“after addition of glass double distilled water to the flasks, they were shaken at approximately 30°C and after standing at 20°C for a period of not less than 24 hours […]” ), considering the weight of evidence as presented in LANXESS (2018), it becomes clear that ZMB2 is not present as such any more, but present as MB2 and zinc ions in water.  Applying the HPLC conditions as done in this study (eluent: acetonitrile with 1% acetic acid), it has to be strongly assumed that ZMB2 will instantly dissociate to MB2  if it did not already undergo this dissociation during the above sample treatment.

Data from this study presents a clear correlation showing increasing pH with increasing ZMB2 concentration dissolved in water, which supports the overall mechanistic conclusion of hydrolytic dissociation of ZMB2 to MB2 (LANXESS, 2018), i.e. :

- the MB2 anion, as a moderate base, reacts with water to raise the pH;

- the resulting increased OH- concentration reacts to a considerable extent with the free zinc ions to form insoluble Zn(OH)2, which precipitates; and,

- as a result, observed zinc in aqueous solution is significantly below what is expected in a mass balance

Water Solubility (GLP, Bayer, 1990) - Supporting Study

This study was not considered in the original 2013 dossier.  In this study, the conclusion drawn was that the substance is not stoichiometrically soluble in water. For that reason, the results for the measured zinc- and MB2- concentration were presented separately.

The fraction of zinc in solution (measured vs. theoretical) is calculated as follows:

MW (MB2) = 164.23 g/mol; MW (Zn2+) = 65.38 g/mol

Measured mean concentrations in water solubility study:

72.61 mg/L MB2 ; 1.33 mg/L Zn2+

From these concentrations the following measured molar ratio results:

0.4421 : 0.0203

= 1 : 0.046

Theoretical molar ratio:

2 : 1

= 1 : 0.5

Result: only approx. 9% (0.046/0.5 = 0.09) of the theoretically expected Zn2+ concentration is dissolved in the aqueous phase. In other words, the dissolved MB2 part was about 22 times higher than the Zn2+ part while a theoretical ratio of 2:1 is expected.

In aqueous solution of ZMB2 at pH 7, ZMB2 is dissolved as MB2 and Zn2+ (LANXESS, 2018). The dissolved Zn2+ mainly precipitates as Zn(OH)2. Only approximately 9% of the theoretically expected Zn2+ concentration is dissolved in the aqueous phase. In other words, for >90% of the MB2 molecules there is no stoichiometric Zn2+ counterpart in solution.

This study demonstrates that ZMB2 is splitting into zinc ions and MB2 rather than being present in undissociated form in aqueous solution. For the dissolved fraction of zinc, formally there is no information available from this study if this is bound to MB2 molecules in solution or dissolved in water as zinc ion. However, from weight of evidence presented in LANXESS (2018), the dissolved fraction of zinc must clearly be assigned to ionic Zn2+ in solution and not to undissociated ZMB2 dissolved as a whole molecule.

The statement in the study report that “Vulkanox ZMB2/C5 is not stoichiometrically soluble in water” could more accurately be worded as follows: “Vulkanox ZMB2 dissolves in a stoichiometric ratio, but the zinc does not remain in solution.”  This means that zinc concentration is not useful as a measurement of ZMB2 concentration in aqueous environments.

Endpoint Conclusion

The conclusion of water solubility = 32 mg/L for this endpoint remains based on the key study, for use in chemical safety assessment.  The soluble organic fraction as a basis for this endpoint has been identified as MB2, with the inorganic fraction (Zn(OH)2) soluble at ~ 1 mg/L based on a supporting study.