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EC number: 818-416-3 | CAS number: 1438425-69-4
Hydrolysis
Administrative data
- Endpoint:
- hydrolysis
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From 04 NOV 2019 to 30 JUN 2020
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 020
- Report date:
- 2020
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 111 (Hydrolysis as a Function of pH)
- Version / remarks:
- adopted 13 April 2004
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
Test material
- Reference substance name:
- methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate compd with dimethylsulfoxide
- EC Number:
- 818-416-3
- Cas Number:
- 1438425-69-4
- Molecular formula:
- C19H16F2N8O2*2C2H6OS
- IUPAC Name:
- methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate compd with dimethylsulfoxide
- Test material form:
- solid
Constituent 1
- Radiolabelling:
- no
Study design
- Analytical monitoring:
- yes
- Details on sampling:
- Tier 1 (preliminary test):
- Sampling intervals for the parent/transformation products: 0, 3, 24 and 120 h
At each sampling, duplicate samples were taken. - Buffers:
- - pH: 4.0
- Type and final molarity of buffer: 0.05 M acetate buffer
- Composition of buffer: 410 mL acetic acid (0.1 M), mixed with 90 mL sodium acetate (0.1 M), added up with water to 1 L
- pH: 7.0
- Type and final molarity of buffer: 0.05 M Tris buffer
- Composition of buffer: 7.92 g Tris(hydroxymethyl)aminomethane dissolved in 900 mL, pH was adjusted using 28-30% ammonia, added up with water to 1 L
- pH: 9.0
- Type and final molarity of buffer: 0.05 M carbonate buffer
- Composition of buffer: 3.96 g ammonium hydrogen carbonate dissolved in 900 mL, pH was adjusted using 28-30% ammonia, added up with water to 1 L - Details on test conditions:
- TEST SYSTEM
- Type, material and volume of test flasks, other equipment used: 10 mL glass flasks
- Sterilisation method: Degassed buffer solutions were sterilized using 0.2 µm filters. Glassware was autoclaved (20 min at 121°C)
- Measures taken to avoid photolytic effects: Incubation in the dark
- Measures to exclude oxygen: purging with inert gas (nitrogen)
Temperature was recorded continuously.
The pH of the samples was determined at each sampling point.
To prevent further degradation, samples were diluted by a factor of 4.
Samples were analyzed without any further treatment such as filtration.
Sterility was assessed at final sampling using a commercially availble dip slide kit to determine total count of bacteria and yeast/moulds.
Duration of testopen allclose all
- Duration:
- 5 d
- pH:
- 4
- Temp.:
- 50 °C
- Initial conc. measured:
- 0.5 mg/L
- Duration:
- 5 d
- pH:
- 7
- Temp.:
- 50 °C
- Initial conc. measured:
- 0.5 mg/L
- Duration:
- 5 d
- pH:
- 9
- Temp.:
- 50 °C
- Initial conc. measured:
- 0.5 mg/L
- Number of replicates:
- 2 samples per sampling time and pH level
- Positive controls:
- no
- Negative controls:
- no
Results and discussion
- Preliminary study:
- At the end of the incubation period of 5 days, recoveries were 96.9, 98.3 and 90.3% of the nominal concentration applied for pH 4, 7 and 9, respectively.
Thus, the BAY 1021189 crude was considered to be hydrolytically stable at all pH levels tested. Based on this, no further testing (Tier 2) was required. - Transformation products:
- not measured
Total recovery of test substance (in %)open allclose all
- % Recovery:
- 96.9
- pH:
- 4
- Temp.:
- 50 °C
- Duration:
- 5 d
- Remarks on result:
- hydrolytically stable based on preliminary test
- % Recovery:
- 98.3
- pH:
- 7
- Temp.:
- 50 °C
- Duration:
- 5 d
- Remarks on result:
- hydrolytically stable based on preliminary test
- % Recovery:
- 90.3
- pH:
- 9
- Temp.:
- 50 °C
- Duration:
- 5 d
- Remarks on result:
- hydrolytically stable based on preliminary test
Dissipation DT50 of parent compoundopen allclose all
- Key result
- pH:
- 4
- Temp.:
- 50 °C
- DT50:
- > 1 yr
- Type:
- (pseudo-)first order (= half-life)
- Key result
- pH:
- 7
- Temp.:
- 50 °C
- DT50:
- > 1 yr
- Type:
- (pseudo-)first order (= half-life)
- Key result
- pH:
- 9
- Temp.:
- 50 °C
- DT50:
- > 1 yr
- Type:
- (pseudo-)first order (= half-life)
- Details on results:
- See above, only Tier 1 performed.
Sterility was confirmed by absence of any countable CFU, neither for bacteria nor yeasts and moulds.
Any other information on results incl. tables
Table 1: Results of preliminary test (Tier 1)
| % Applied concentration | |||
| Incubation period [h] | Replicate | [% nominal] | mean |
| pH 4.0 | |||
| 0 | A B |
94.6 94.1 |
94.3 |
| 3 | A B |
91.3 93.7 |
92.5 |
24 |
A B |
92.2 94.3 |
93.3 |
120 |
A B |
97.5 96.3 |
96.9 |
pH 7.0 |
|||
0 |
A B |
99.0 98.4 |
98.7 |
3 |
A B |
97.9 98.8 |
98.3 |
24 |
A B |
99.5 106.4 |
102.9 |
120 |
A B |
97.6 98.9 |
98.3 |
pH 9.0 |
|||
0 |
A B |
94.7 95.9 |
95.3 |
3 |
A B |
94.6 97.1 |
95.8 |
24 |
A B |
99.8 100.8 |
100.3 |
120 |
A B |
91.3 89.3 |
90.3 |
Applicant's summary and conclusion
- Validity criteria fulfilled:
- yes
- Remarks:
- Recoveries at all pH levels were within a range of 90 - 110%.
- Conclusions:
- As the recovery of BAY 1021189 crude was ranging from 90.3 to 98.3% of nominal applied concentration at three different pH levels, the test item is considered to be hydrolytically stable (t(0.5) > 1 year at 25°C)
- Executive summary:
In a GLP study performed according to OECD TG 111, hydrolysis of BAY 1021189 crude was assessed as a function of pH.
To this the concentration of the test item at 0, 3, 24 and 120 hours incubation at 50°C in the dark was assessed in duplicate at pH levels of 4, 7 and 9.
All validity criteria were fulfilled and sterility of samples was demonstrated by the absence of countable bacteria or yeasts/moulds.
A preliminary test (Tier 1) resulted in recoveries of 96.9, 98.3 and 90.3% of nominal concentration applied at pH levels of 4, 7 and 9, respectively. Based on these results, BAY 1021189 crude is considered to be hydrolytically stable and a half-life exceeding 1 year at 25°C can be estimated and no Tier 2 testing was necessary.
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