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Partition coefficient

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Endpoint:
partition coefficient
Type of information:
experimental study
Adequacy of study:
key study
Study period:
March 2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study conducted to OECD guideline.
Qualifier:
according to
Guideline:
OECD Guideline 107 (Partition Coefficient (n-octanol / water), Shake Flask Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Type of method:
shake-flask method to: flask method
Partition coefficient type:
octanol-water
Analytical method:
high-performance liquid chromatography
Type:
Pow
Partition coefficient:
1 170
Temp.:
20.5 °C
pH:
>= 6.3 - <= 6.5
Key result
Type:
log Pow
Partition coefficient:
3.07
Temp.:
20.5 °C
pH:
>= 6.3 - <= 6.5
Details on results:
- Preliminary estimates:
Approximate solubility in n-octanol = >2.07 g/l
Approximate solubility in water = <1.40E-3 g/l
Approximate Pow = >1.48E-3 g/l
Log10 Pow = >3.17

- Validation:
Linearities of the detector response with respect to concentration were assessed over the nominal concentration range of 0 to 100 mg/l for the organic matrix and 0 to 2 mg/l for the aqueous matrix. These were satisfactory with correlation coefficients of 1.000 and 0.998 being obtained for the organic and aqueous matrices respectively.

Table 2 Organic phase

Solutions

Mean peak area

Standard 50.2 mg/l

2.79E+03

Standard 50.4 mg/l

2.79E+03

Sample 1

2.73E+03

Sample 2

2.74E+03

Sample 3

2.76E+03

Sample 4

2.77E+03

Sample 5

2.76E+03

Sample 6

2.77E+03

Stock Solution A

2.77E+03

Stock Solution B

2.77E+03

Table 3 Aqueous phase

Solutions

Mean peak area

Standard 1.00 mg/l

55.31

Standard 1.01 mg/l

5.29

Sample 1

25.91

Sample 2

28.47

Sample 3

24.51

Sample 4

22.42

Sample 5

51.51

Sample 6

19.91

Table 4 Total weights (mg) and analysed concentration (mg/l)

 

 

 

 

Organic phase

Aqueous phase

 

Sample number

Volume of stock solution (mL)

Volume of n-octanol Saturated water (mL)

Total weight (mg)

Analysed concentration (mg/L)

Total weight (mg)

Analysed concentration

(mg/L)

Total weight (mg)

pH

1

60

60

60.0

987

59.2

0.943

5.66E-02

6.2

2

960

60

60.0

991

59.5

1.04

6.22E-02

6.3

3

90

45

90.0

997

89.7

0.892

4.01E-02

6.4

4

90

45

90.0

1.00E+03

90.1

0.816

3.67E-02

6.4

5

45

90

45.0

995

44.8

0.783

7.04E-02

6.5

6

45

90

45.0

1.00E+03

45

0.724

6.52E-02

6.5

Table 5 Partition coefficent

Sample number

n-octanol:water volume ratio

Partition coefficient

log10 Pow

Mean partition coefficient

1

1:1

1.05E+03

3.02

1.00E+03

2

957

2.98

3

2:1

1.12E+03

3.05

1.17E+03

4

1.23E+03

3.09

5

1:2

1.27E+03

3.10

1.33E+03

6

1.38E+03

3.14

 

Conclusions:
The partition coefficient of the test material has been determined to be 1.17E3 at 20.5 +/- 0.5 degC, log10 Pow 3.07.
Endpoint:
partition coefficient
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1991-04-29 till 1991-06-14
Qualifier:
according to
Guideline:
OECD Guideline 107 (Partition Coefficient (n-octanol / water), Shake Flask Method)
Deviations:
not specified
GLP compliance:
yes
Type of method:
flask method
Partition coefficient type:
octanol-water
Key result
Type:
Pow
Partition coefficient:
>= 120.5 - <= 548.2
Temp.:
22.1 °C
pH:
6.6
Details on results:
When the Pow was determined on the basis of the zinc concentration, there is a strong dependency of the Pow from the share of the octanol phase compared to the share of water (548.2 for high share of octanol vs. 120.5 for low share of octanol).

A Pow with a minimum of 120.5 based on zinc concentration on the one hand suggests that undissociated ZMB2 is present in the organic phase. On the other hand, the absolute (supposed) ZMB2 amount (given in above table; based on zinc concentration) dissolved in the aqueous phase basically remains the same even if the share of octanol is increased by a factor of ~4 compared to the lowest octanol share.  This suggests that zinc is to the largest part dissolved as Zn2+, the zinc concentration being unaffected by the amount of organic phase present in the two-phase system.

Table 1. Zinc content

 

 

Volume

Concentration

Individual partition-coefficient

Mean partition-coefficient

Run no.

pH (water phase)

Octanol phase (mL)

Water phase (mL)

Octanol phase (mg/mL)

Water phase (mg/mL)

1a

6.6

5.0

245

8.54 mg =

1.678

0.76 mg =

3.06*10-3

549.1

548.2

1b

6.6

5.0

245

1.738

3.18*10-3

547.2

2a

6.6

10.0

240

8.39 mg =

0.839

0.82 mg =

3.78*10-3

222.3

248.4

2b

6.6

10.0

240

0.839

3.06*10-3

274.5

3a

6.6

20

230

8.14 mg =

0.413

0.78 mg =

3.54*10-3

113.4

120.5

3b

6.6

20

230

0.413

3.24*10-3

127.6

Conclusions:
When the Pow was determined on the basis of the zinc concentration, there is a strong dependency of the Pow from the share of the octanol phase comprared to the share of water (548.2 for high share of octanol vs. 120.5 for low share of octanol).
Endpoint:
partition coefficient
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2011-07-26 till 2011-08-18
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to
Guideline:
EU Method A.8 (Partition Coefficient)
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 117 (Partition Coefficient (n-octanol / water), HPLC Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Type of method:
HPLC method
Partition coefficient type:
octanol-water
Analytical method:
high-performance liquid chromatography
Type:
log Pow
Partition coefficient:
0.3
Temp.:
25 °C
pH:
5.8
Remarks on result:
other: Fraction 1: Retention time tR (min): 5.039, Area (%): 6.86
Type:
log Pow
Partition coefficient:
0.4
Temp.:
25 °C
pH:
5.8
Remarks on result:
other: Fraction 2: Retention time tR (min): 5.254, Area (%): 10.5
Details on results:
The chromatogram of the test item 1,3-Dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione showed 2 signals eluting from 5.0 to 5.3 minutes. No calibration substance with a Pow- value below the value for the signals of the test item was available. For this reason the results for these signals were extrapolated.

Although the determined value does not exactly meet the range of application of the test guideline (0.3 – 6.2), we consider the value as valid (measurement uncertainty +/- 0,5 log units).
Conclusions:
The log Pow was determinated at 25 °C in the range of 0.3 to 0.4.
Executive summary:

The partition coefficient was determined by using OECD 117 HPLC method. The chromatogram showed a mixture of 2 partially resolved peaks corresponding to 2 fractions with the log Pow from 0.3 to 0.4. In order to ensure a stable performance of the HPLC column, the column temperature was set to 40 °C. However, the temperature of the log Pow of the test substance is dependent on the one of reference substance; and hence the determined log Pow is at 25 °C.

Endpoint:
partition coefficient
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Refer to Section 13.2 for read-across justification document.
Reason / purpose:
read-across source
Key result
Type:
log Pow
Partition coefficient:
0.3
Temp.:
25 °C
pH:
5.8
Remarks on result:
other: Fraction 1: Retention time tR (min): 5.039, Area (%): 6.86
Key result
Type:
log Pow
Partition coefficient:
0.4
Temp.:
25 °C
pH:
5.8
Remarks on result:
other: Fraction 2: Retention time tR (min): 5.254, Area (%): 10.5
Details on results:
The chromatogram of the test item 1,3-Dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione showed 2 signals eluting from 5.0 to 5.3 minutes. No calibration substance with a Pow- value below the value for the signals of the test item was available. For this reason the results for these signals were extrapolated.

Although the determined value does not exactly meet the range of application of the test guideline (0.3 – 6.2), we consider the value as valid (measurement uncertainty +/- 0,5 log units).
Conclusions:
The log Pow was determinated at 25 °C in the range of 0.3 to 0.4.
Executive summary:

In a one-to-one read-across approach, the substance 1,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione (source substance) is considered appropriate for direct read-across (one-to-one) to zinc 4-methyl-2-thioxo-2,3-dihydrobenzimidazol-1-ide 7-methyl-2-thioxo-2,3-dihydrobenzimidazol-1-ide (target substance) for the endpoint partition coefficient. In conclusion, the log Pow was determinated at 25 °C in the range of 0.3 to 0.4. A full justification for the read-across approach is presented in IUCLID Section 13.2.

Description of key information

Key Study:

Log Pow = 3.07 (20.5 °C, pH = 6.3 - 6.5); OECD 107 - shake flask; Safepharm (2004)

Supporting Study:

Log Pow = 2.08 - 2.74 (22.1 °C, pH = 6.6); OECD 107 - shake flask; Bayer (1991)

Log Pow = 0.3 - 0.4 (25 °C); OECD 117 (HPLC); Currenta (2011) - read-across from 1,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione (MB2)

Key value for chemical safety assessment

Log Kow (Log Pow):
0.4
at the temperature of:
25 °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 n-octanol/water partition coefficient 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 relating to partition coefficient, refer to Section 13.2 of IUCLID.

Note that ZMB2 is assumed to be stable in octanol as characteristic NMR spectra of ZMB2 were obtained in d6-DMSO, d6-acetone, d1-acetonitrile and - especially noteworthy in that context – in d3-methanol. The characteristic signal pattern vanishes after the addition of trifluoroacetic acid, leading to MB2 as demonstrated by suitable NMR measurements

Partition Coefficient Study (GLP, SafePharm, 2004) - Key Study

This is used as the key study for the partition coefficient endpoint (log Pow = 3.07), as it is the newest study with a more detailed study report compared to older studies.  

In this study a stock solution was prepared by diluting test material (0.5017g) to 500 ml with water saturated n-octanol.  It is assumed that ZMB2 is stable in water-saturated n-octanol, first considering the stability of ZMB2 when a NMR is acquired in methanol, secondly because the obtained value of log Pow = 3.07 is significantly higher than the values measured for the two MB2 isomers (log Pow = 0.3 - 0.4).  

The shaking was performed by inversion of the flasks through approximately 180° over 5 minutes.  In this short time frame, only limited transfer of undissociated ZMB2 from the octanol phase to the aqueous phase, where MB2 instantly dissociates (LANXESS, 2018) and Zn2+ precipitates as hydroxide to a considerable extent, is assumed.

HPLC conditions: Mobile phase: acetonitrile:water (35:65 v/v), containing 0.1% acetic acid.  Under these aqueous acidic conditions, ZMB2 will instantly dissociate to MB2 (LANXESS, 2018). Thus indeed the partitioning between octanol and water is determined by measuring the respective concentrations of MB2 in each phase following instant dissociation on the HPLC column if not already dissociated earlier. ZMB2 is deemed stable in the octanol phase, while the ZMB2 fraction in the aqueous phase in fact dissociated already prior to HPLC measurement.

Partition Coefficient Study (GLP, Bayer, 1991) - Supporting Study

This is used as a supporting study for the partition coefficient endpoint (log Pow = 2.08 - 2.74).  

In this study the partition coefficient is calculated both from the zinc concentration as well as from the concentration of MB2. The strongly scattering results from determination of the zinc content could indicate on the one hand a dependency of the Pow from the application concentration, but on the other hand be influenced by the composition of the starting product (test item). For example, if the test item contains residual amounts of zinc salts, the concentration in the aqueous phase will strongly depend on these residual amounts.

Based on the results of this study, the following interpretations/conclusions derived:

When the Pow was determined on the basis of the zinc concentration, there is a strong dependency of the Pow from the share of the octanol phase compared to the share of water (548.2 for high share of octanol vs. 120.5 for low share of octanol).  Based on LANXESS (2018) it is interpreted that a Pow with a minimum of 120.5 based on zinc concentration on the one hand suggests that undissociated ZMB2 is present in the organic phase. On the other hand, the absolute (supposed) ZMB2 amount (based on zinc concentration) dissolved in the aqueous phase basically remains the same even if the share of octanol is increased by a factor of 4 compared to the lowest octanol share.  This suggests that zinc is to the largest part dissolved as Zn2+, the zinc concentration being unaffected by the amount of organic phase present in the two-phase system.

When the Pow was determined on the basis of HPLC (unknowingly measuring MB2 instead of ZMB2 if an acidic and or aqueous HPLC solvent is used), there was only limited dependency of the Pow from the share of the octanol phase.  The absolute (supposed) amount of ZMB2 (based on HPLC) dissolved in the aqueous phase decreases approximately in the same way that the share of organic phase is increased. The decrease of (supposedly) the amount of ZMB2 in the aqueous phase fits well with the corresponding increase in the organic phase.  This however, is in strong contrast to the behavior of the (supposed) ZMB2 amount based on zinc concentration in the aqueous phase.

Comparing the data generated for Pow determination based on zinc and HPLC measurement (of MB2), the following conclusion is drawn:

- The results based on HPLC are in agreement with the interpretation of the Pow results as determined on the basis of the zinc concentration: ZMB2 in the aqueous phase is to the largest part dissolved as Zn2+ and MB2, the latter as judged by its log Pow of 0.3 to 0.4 (for the respective two isomers) clearly affected by the amount of organic phase present in the 2-phase system – in contrast to the Zn2+ ion.

Overall Endpoint Considerations

In the study by Bayer (1991) a lower log Pow of 2.6 was determined while partitioning (shaking) between the phases in this study for 60 minutes, greater than the 5 minutes applied in the SafePharm (2004) study (log Pow = 3.07). This observation is consistent with the interpretation of a higher transfer of undissociated ZMB2 from the octanol phase to the aqueous phase, where ZMB2 instantly dissociates to MB2 (lower log Pow of 0.3-0.4) and Zn2+ precipitates as hydroxide to a considerable extent.  This would effectively lead to more MB2 in the aqueous phase which was interpreted as ZMB2 in both log Pow studies. Thus longer partitioning is expected to lead to a seemingly lower log Pow when in fact MB2 is measured via HPLC instead of ZMB2.

A measured value of log Pow = 3.07 (SafePharm, 2004) is not used as the overall endpoint conclusion as the log Pow for MB2 of 0.4, is considered relevant for PNEC determination and bioaccumulation assessment as MB2 is the relevant species for the aquatic environmental compartment, given the hydrolytic instability of ZMB2, forming MB2 and inorganic zinc (Zn(OH)2) under aqueous conditions.  A partition coefficient for Zn(OH)2 is not relevant when considering bioaccumulation potential as this substance is inorganic.

Supporting Study for Partition Coefficient of MB2 (Currenta, 2011)

The partition coefficient 0f MB2 was determined by using OECD 117 HPLC method. The chromatogram showed a mixture of 2 partially resolved peaks corresponding to 2 fractions with the log Pow from 0.3 to 0.4. In order to ensure a stable performance of the HPLC column, the column temperature was set to 40 °C. However, the temperature of the log Pow of the test substance is dependent on the one of reference substance; and hence the determined log Pow is at 25 °C.