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Diss Factsheets

Administrative data

Endpoint:
hydrolysis
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2019-01-29 to 2019-09-18
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019
Report date:
2019

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 111 (Hydrolysis as a Function of pH)
Version / remarks:
2004
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
5-fluoro-1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile
EC Number:
811-889-7
Cas Number:
1350653-26-7
Molecular formula:
C14 H8 F2 N4
IUPAC Name:
5-fluoro-1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile
Test material form:
solid
Radiolabelling:
no

Study design

Analytical monitoring:
yes
Details on sampling:
Preliminary Test (Tier 1)
Sampling of the Test Samples: pH 4, 7 (carbonate and Tris) and 9: 0, 3, 24, 120 h
At each sampling point, samples were taken in duplicate.
Main Test (Tier 2)
Sampling of the Test Samples:
pH 4:
20°C: 0 h, 1 d, 3 d, 7 d, 10 d, 14 d, 17 d, 24 d, 31 d
60°C: 1 d, 3 d, 7 d, 10 d, 14 d, 17 d, 24 d, 31 d
pH 7:
20°C: 0 h, 1 d, 3 d, 7 d, 10 d, 14 d, 17 d, 24 d, 31 d
60°C: 1 d, 3 d, 7 d, 10 d, 14 d, 17 d, 24 d, 31 d
pH 9:
20°C: 0 h, 1 d, 3 d, 7 d, 10 d, 14 d, 17 d, 24 d, 31 d
60°C: 1 d, 2 d, 3 d, 4 d, 7 d, 10 d, 14 d, 17 d, 24 d, 31 d
At each sampling point, samples were taken in duplicate.
Buffers:
Sterile aqueous solutions buffered at pH 4, 7 and 9.
The pH of each buffer solution was measured with a calibrated pH meter. Buffers were either prepared freshly or in course of other projects (131561293, 127171293).
pH 4: 0.05 M acetate buffer
205 mL and 410 mL acetic acid (0.1 M) was added to 45 mL and 90 mL sodium acetate (0.1 M), respectively. The solution was filled up to 500 mL and 1000 mL with pure water, respectively.
pH 7: 0.05 M carbonate buffer
3.98 g of ammonium hydrogen carbonate was added to 1000 mL of pure water.
pH 7: 0.05 M Tris buffer
3.94 g and 7.89 g of Tris-HCl was added to 500 mL and 1000 mL of pure water, respectively.
pH 9: 0.05 M carbonate buffer
3.96 g of ammonium hydrogen carbonate was added to 1000 mL of pure water.
Details on test conditions:
Temperature:
Preliminary test (Tier 1): 50°C ± 0.5°C
Main test (Tier 2): 20°C ± 0.5°C; 60°C ± 2.8°C
Light Conditions:
The samples were incubated in the dark.
Anoxic Conditions:
To avoid oxidation the buffer solutions were purged with inert gas (nitrogen) prior to sterilisation.
Sterile Conditions:
Prior to application, degased buffer solutions were sterilised by filtration (0.2 µm). The used glassware was sterilised using an autoclave (20 min at 121°C) or heated in an oven (180°C, > 3 h).
Duration of testopen allclose all
Duration:
31 d
pH:
4
Temp.:
20
Initial conc. measured:
0.855 mg/L
Duration:
31 d
pH:
4
Temp.:
60
Initial conc. measured:
0.855 mg/L
Duration:
31 d
pH:
7
Temp.:
20
Initial conc. measured:
0.699 mg/L
Duration:
31 d
pH:
7
Temp.:
60
Initial conc. measured:
0.699 mg/L
Duration:
31 d
pH:
9
Temp.:
20
Initial conc. measured:
0.767 mg/L
Duration:
17 d
pH:
9
Temp.:
60
Initial conc. measured:
0.767 mg/L
Number of replicates:
Two samples of solutions of each pH value at each test temperature were taken at each sampling point.
Positive controls:
no
Negative controls:
no

Results and discussion

Preliminary study:
Samples were incubated at three different pH-values and at one temperature. The test was carried out for 5 days. Recoveries at the end of incucation were 87.9% of the nominal applied concentration for pH 4, 81.5% for pH 7 and 67.4% for pH 9. The main test (Tier 2) was performed at pH 4, 7 and 9. Values given are averages obtained from duplicate samples.
Test performance:
1) Concerning (Study Plan): 2.2.3 Test Conditions, page 7
According to Study Plan: The temperatures will be maintained to at least ± 0.5°C.
Deviation to Study Plan: Main test (Tier 2): 60°C ± 2.8°C
Reason for Deviation: Technical reason.
Presumed Effect on the Study: None. The deviation was of minor extent (mean temperature during incubation: 60°C).
2) Concerning (Study Plan): 2.4.1 Test Procedure, page 8
According to Study Plan: Main Test (Tier 2):
A main test will be carried out at three selected temperatures in the range of 10-70°C (including 50°C).
Deviation to Study Plan: The test was performed with two temperatures (20 and 60°C)
Reason for Deviation: Significant distribution of values obtained at 20 and 60°C.
Presumed Effect on the Study: The temperatures tested spanning the range of standard conditions (20°C) to harsh conditions (60°C) and thus it was considered acceptable to sufficiently assessed the hydrolytic behaviour of the test item.
3) Concerning (Study Plan): 2.7.3 Analytical Methods, page 10
According to Study Plan: LC-MS/MS-Conditions:
Column: Phenomenex, Synergi Polar-RP 80A, 150x3.0 mm, 4 µm; Pre-Column:C18
Deviation to Study Plan: Pre-Column was not used.
Reason for Deviation: Error.
Presumed Effect on the Study: None. Chromatographic behaviour of the test item is equal with and without a pre-column installed.
4) Concerning (Study Plan): 2.8.1 Validation Parameters of the Study, page 11
According to Study Plan: Immediately after application the recovery should be in the range of 70-110% (preferably 90-110%) of the nominal applied concentration.
Deviation to Study Plan: At pH 4 (Tier 2), the recovery was out of the required range.
Reason for Deviation: A reason could not be stated.
Presumed Effect on the Study: Values were considered acceptable for further calculations. To determine the hydrolysis parameters (e.g. DT50) calculations were based on the applied concentration at 0 h, which means that all recoveries refer to the mean value at 0h.
Transformation products:
not measured
Total recovery of test substance (in %)open allclose all
% Recovery:
82.7
pH:
4
Temp.:
20 °C
Duration:
31 d
% Recovery:
87.4
pH:
4
Temp.:
60 °C
Duration:
31 d
% Recovery:
97.2
pH:
7
Temp.:
20 °C
Duration:
31 d
% Recovery:
49.4
pH:
7
Temp.:
60 °C
Duration:
31 d
% Recovery:
65.9
pH:
9
Temp.:
20 °C
Duration:
31 d
% Recovery:
0.8
pH:
9
Temp.:
60 °C
Duration:
17 d
Dissipation DT50 of parent compoundopen allclose all
pH:
4
Temp.:
20 °C
Hydrolysis rate constant:
0.007 d-1
DT50:
94.5 d
Type:
not specified
pH:
4
Temp.:
60 °C
Hydrolysis rate constant:
0.012 d-1
DT50:
57.3 d
Type:
not specified
pH:
7
Temp.:
20 °C
Hydrolysis rate constant:
0 d-1
DT50:
> 10 000 d
Type:
not specified
Remarks on result:
other: y = 0.0030 * x - 0.0054; r² = 0.9929
pH:
7
Temp.:
60 °C
Hydrolysis rate constant:
0.027 d-1
DT50:
26.2 d
Type:
not specified
Remarks on result:
other: y = 0.0259 * x - 0.0058; r² = 0.9996
pH:
9
Temp.:
20 °C
Hydrolysis rate constant:
0.013 d-1
DT50:
52.1 d
Type:
not specified
Remarks on result:
other: y = 0.0410 * x - 0.1311; r² = 0.9771
pH:
9
Temp.:
60 °C
Hydrolysis rate constant:
0.211 d-1
DT50:
3.29 d
Type:
not specified
Remarks on result:
other: y = 0.3360 * x - 0.0481; r² = 0.9996
Details on results:
Samples were incubated at 20 and 60°C. Based on the kinetic result evaluation a third temperature (50°C) was not tested (in agreement with the Sponsor). However, the temperatures tested spanning the range of standard conditions (20°C) to harsh conditions (60°C) and thus it was considered acceptable to sufficiently assessed the hydrolytic behaviour of the test item.
Values given are averages obtained from duplicate samples.
pH4
The test was carried out for 31 days. During incubation the concentration of the test item decreased. At the end of incubation recoveries were 67.8% and 71.6% of the nominal applied concentration at 20 and 60°C, respectively.
Hydrolysis rate constants and corresponding DT50 and DT90 values for the test item were determined for each temperature:
20°C: k = 0.0733 d-1 ;DT50 = 94.5 d; DT90 = 314.0 d
60°C: k = 0.0121 d-1 ;DT50 = 57.3 d; DT90 = 190.0 d
The hydrolysis rate constant and the corresponding DT50 value was calculated for a temperature of 25°C based on the arrhenius parameters:
25°C: k = 0.008 d-1 ;DT50 = 88.1 d
pH7
The test was carried out for 31 days. During incubation the concentration of the test item decreased at 60°C and remained stable at 20°C. At the end of incubation recoveries were 97.2% and 49.4% of the nominal applied concentration at 20 and 60°C, respectively.
Hydrolysis rate constants and corresponding DT50 and DT90 values for the test item were determined for each temperature:
20°C: k = 7.36*10-13 d-1 ;DT50 = >10000 d; DT90 = >10000 d
60°C: k = 0.0265 d-1 ;DT50 = 26.2 d; DT90 = 86.9 d
The hydrolysis rate constant and the corresponding DT50 value was calculated for a temperature of 25°C based on the arrhenius parameters:
25°C: k = 2.19*10-11 d-1 ;DT50 = >10000 d
pH9
The test was carried out for 31 days. During incubation the concentration of the test item decreased. Recoveries were 65.9% (after 31 days) and 0.8% (after 17 days) of the nominal applied concentration at 20 and 60°C, respectively.
Hydrolysis rate constants and corresponding DT50 and DT90 values for the test item were determined for each temperature:
20°C: k = 0.0133 d-1 ;DT50 = 52.1 d; DT90 = 173.0 d
60°C: k = 0.2107 d-1 ;DT50 = 3.3 d; DT90 = 10.9 d
The hydrolysis rate constant and the corresponding DT50 value was calculated for a temperature of 25°C based on the arrhenius parameters:
25°C: k = 0.020 d-1 ;DT50 = 35.4 d

Applicant's summary and conclusion

Validity criteria fulfilled:
yes
Remarks:
% of the nominal applied concentration: Pre-test (Tier 1): 88.6-104.5%; Main test (Tier 2): pH 4: 122.1%, pH 7: 99.8%, pH 9: 109.6% At pH 4 values were considered acceptable for calculations which were based on the applied concentration at 0 h.
Conclusions:
At 20°C the test item was found to be hydrolytically stable at pH 7 (DT50 > 1 year at 25°C) and hydrolytically unstable at pH 4 and 9. Under harsh conditions (60°C) the test item was found to be hydrolytically unstable at each tested pH.
The main test (Tier 2) was performed at pH 4, 7 and 9 and two temperatures (20 and 60°C). Based on the kinetic result evaluation a third temperature (50°C) was not tested (in agreement with the Sponsor). However, the temperatures tested spanning the range of standard conditions (20°C) to harsh conditions (60°C) and thus it was considered acceptable to sufficiently assessed the hydrolytic behaviour of the test item. At the end of incubation, recoveries (mean) were 67.8% and 71.6% of the nominal applied concentration at 20 and 60°C for pH 4, respectively and 97.2% and 49.4% of the nominal applied concentration at 20 and 60°C for pH 7, respectively. At pH 9 recoveries were 65.9% (after 31 days) and 0.8% (after 17 days) of the nominal applied concentration at 20 and 60°C, respectively.
Executive summary:

This study is classified acceptable and satisfies the guideline requirements for hydrolysis studies.Title: Fluorpyridonitril: Hydrolysis as a Function of pH [OECD 111]

Test Item: Fluorpyridonitril

Guidelines/Recommendations:

This study was based on the procedures indicated by the following internationally accepted guidelines and recommendations:

OECD Guideline for Testing of Chemicals No. 111: "Hydrolysis as a function of pH", adopted April 13, 2004.

GLP: Yes (certified laboratory)

Purpose: The purpose of the study was to determine the rate of hydrolysis of Fluorpyridonitril at different environmentally relevant pH-values and at different temperatures.

Test Setup: Test Vessels:

Glass flasks were used for the test.

Aqueous Solution:

Sterile aqueous solutions buffered at pH 4, 7 and 9.

Test Conditions:

In the dark at,

Preliminary test (Tier 1): 50°C ± 0.5°C

Main test (Tier 2): 20°C ± 0.5°C; 60°C ± 2.8°C

Treatment Rate: 0.7 mg/L (two individual replicates)

 

Results:

At 20°C the test item was found to be hydrolytically stable at pH 7 (DT50 > 1 year at 25°C) and hydrolytically unstable at pH 4 and 9. Under harsh conditions (60°C) the test item was found to be hydrolytically unstable at each tested pH.

The main test (Tier 2) was performed at pH 4, 7 and 9 and two temperatures (20 and 60°C). Based on the kinetic result evaluation a third temperature (50°C) was not tested (in agreement with the Sponsor). However, the temperatures tested spanning the range of standard conditions (20°C) to harsh conditions (60°C) and thus it was considered acceptable to sufficiently assessed the hydrolytic behaviour of the test item. At the end of incubation, recoveries (mean) were 67.8% and 71.6% of the nominal applied concentration at 20 and 60°C for pH 4, respectively and 97.2% and 49.4% of the nominal applied concentration at 20 and 60°C for pH 7, respectively. At pH 9 recoveries were 65.9% (after 31 days) and 0.8% (after 17 days) of the nominal applied concentration at 20 and 60°C, respectively.

pH4:

The test was carried out for 31 days. During incubation the concentration of the test item decreased. At the end of incubation recoveries were 67.8% and 71.6% of the nominal applied concentration at 20 and 60°C, respectively.

Hydrolysis rate constants and corresponding DT50 and DT90 values for the test item were determined for each temperature:

20°C: k = 0.0733 d-1 ;DT50 = 94.5 d; DT90 = 314.0 d

60°C: k = 0.0121 d-1 ;DT50 = 57.3 d; DT90 = 190.0 d

The hydrolysis rate constant and the corresponding DT50 value was calculated for a temperature of 25°C based on the arrhenius parameters:

25°C: k = 0.008 d-1 ;DT50 = 88.1 d

pH7:

The test was carried out for 31 days. During incubation the concentration of the test item decreased at 60°C and remained stable at 20°C. At the end of incubation recoveries were 97.2% and 49.4% of the nominal applied concentration at 20 and 60°C, respectively.

Hydrolysis rate constants and corresponding DT50 and DT90 values for the test item were determined for each temperature:

20°C: k = 7.36*10-13 d-1 ;DT50 = >10000 d; DT90 = >10000 d

60°C: k = 0.0265 d-1 ;DT50 = 26.2 d; DT90 = 86.9 d

The hydrolysis rate constant and the corresponding DT50 value was calculated for a temperature of 25°C based on the arrhenius parameters:

25°C: k = 2.19*10-11 d-1 ;DT50 = >10000 d

pH9:

The test was carried out for 31 days. During incubation the concentration of the test item decreased. Recoveries were 65.9% (after 31 days) and 0.8% (after 17 days) of the nominal applied concentration at 20 and 60°C, respectively.

Hydrolysis rate constants and corresponding DT50 and DT90 values for the test item were determined for each temperature:

20°C: k = 0.0133 d-1 ;DT50 = 52.1 d; DT90 = 173.0 d

60°C: k = 0.2107 d-1 ;DT50 = 3.3 d; DT90 = 10.9 d

The hydrolysis rate constant and the corresponding DT50 value was calculated for a temperature of 25°C based on the arrhenius parameters:

25°C: k = 0.020 d-1 ;DT50 = 35.4 d

This study is classified acceptable and satisfies the guideline requirements for hydrolysis studies.