(2S)-3-Methyl-2-[N-({2'-(1H-1,2,3,4-tetrazol-5-yl)-[1,1-biphenyl]-4-yl}methyl)pentanamido]alkanoic acid

Hydrolysis

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Oct 1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EU Method C.7 (Degradation: Abiotic Degradation: Hydrolysis as a Function of pH)

Qualifier:

according to guideline

Guideline:

OECD Guideline 111 (Hydrolysis as a Function of pH)

GLP compliance:

yes

Radiolabelling:

no

Analytical monitoring:

yes

Details on sampling:

Aliquots of each test solution were analysed in time intervals using the analytical method as described later in this report.

Buffers:

Buffer solutions with the following concentrations were used for experiments:
pH4.0: 0.40 vol% 0.1 M NaOH
50.00 vol% 0.1 M potassium biphthalate
49.60 vol% double distilled water
pH7.0: 29.63 vol% 0.1 M NaOii
50.00 vol% 0.1 M monopotassium phosphate
20.37 vol% double distilled water
pH9.0: 21.30 vol% 0.1 M NaOH
50.00 vol% 0.1 M boric acid
28.70 vol% double distilled water
The pH of each buffer solution was checked with a calibrated pH meter at rerequired temperature to a precision of at least ± 0 .1 before and after addition of the test article.

Estimation method (if used):

A preliminary test was performed at 50 °C ± 0.1 °Cat pH 4.0, pH 7.0 and pH 9.0, each. Aliquots of each test solution were analysed in time intervals using the analytical method as described later in this report.

Details on test conditions:

As described in the guideline, in accordance with the RCC Umweltchemie Standard Operating Procedures. Incubation time of 5 days.

Duration:

5 d

pH:

4

Temp.:

25 °C

Initial conc. measured:

>= 0.127 - <= 42.7 mg/L

Duration:

5 d

pH:

7

Temp.:

25 °C

Initial conc. measured:

>= 0.127 - <= 42.7 mg/L

Duration:

5 d

pH:

9

Temp.:

25 °C

Initial conc. measured:

>= 0.127 - <= 42.7 mg/L

Preliminary study:

The preliminary test for a hydrolysis reaction of CGP 48933 Step 9 at pH 4.0, pH 7.0 and pH 9.0 was performed according to the OECD guideline no. 111: "Hydrolysis as a function of pH" {1981) and the EEC directive 92/69, C.7: " Abiotic degradation: hydrolysis as a function of pH" (1992).

Transformation products:

not specified

% Recovery:

<= 10

pH:

4

Temp.:

25 °C

Duration:

5 d

Remarks on result:

hydrolytically stable based on preliminary test

% Recovery:

<= 10

pH:

7

Temp.:

25 °C

Duration:

5 d

Remarks on result:

hydrolytically stable based on preliminary test

% Recovery:

<= 10

pH:

9

Temp.:

25 °C

Duration:

5 d

Remarks on result:

hydrolytically stable based on preliminary test

Key result

pH:

4

Temp.:

25 °C

Type:

not specified

Remarks on result:

hydrolytically stable based on preliminary test

Key result

pH:

7

Temp.:

25 °C

Type:

not specified

Remarks on result:

hydrolytically stable based on preliminary test

Key result

pH:

9

Temp.:

25 °C

Type:

not specified

Remarks on result:

hydrolytically stable based on preliminary test

Validity criteria fulfilled:

yes

Conclusions:

The results showed no significant degradation of CGP 48933 Step 9. Because less than 10 % of the hydrolysis reaction was observed after 5 days at pH 4.0, pH 7.0 and pH 9.0 respectively, CGP 48933 Step 9 was considered to be hydrolytically stable. Therefore no further testing was necessary at these pH values.

The half-life times of CGP 48933 Step 9 at pH 4.0, pH 7.0 and pH 9.0 were estimated to be longer than one year at 25 °C (tv. (25 °C) > 1 year).

Reference 2

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Dec 2018 - March 2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 111 (Hydrolysis as a Function of pH)

Qualifier:

according to guideline

Guideline:

EU Method C.7 (Degradation: Abiotic Degradation: Hydrolysis as a Function of pH)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 835.2120 (Hydrolysis of Parent and Degradates as a Function of pH at 25°C)

GLP compliance:

yes

Radiolabelling:

no

Analytical monitoring:

yes

Details on sampling:

The concentration of the test item in the test samples was determined immediately after preparation (t=0) and after 2.4 hours and 5 days. The samples taken after 2.4 hours and 5 days were cooled to room temperature using running tap water.

Buffers:

Acetate buffer pH 4, 0.1 M
Solution of 16.7% 0.1 M sodium acetate in water and 83.3% 0.1 M acetic acid in water. Buffer contained 0.0009% (w/v) sodium azide.
Phosphate buffer pH 7, 0.1 M
Solution of 0.1 M potassium di-hydrogenphosphate in water adjusted to pH 7 using 10N sodium hydroxide. Buffer contained 0.0009% (w/v) sodium azide.
Borate buffer pH 9, 0.1 M
Solution of 0.1 M boric acid in water and 0.1M potassium chloride in water adjusted to pH 9 using 10N sodium hydroxide. Buffer contained 0.0009% (w/v) sodium azide.

Details on test conditions:

The buffer solutions were filter-sterilised through a 0.2 μm FP 30/0.2 CA-S filter (Whatman, Dassel, Germany) and transferred into a sterile vessel. To exclude oxygen, nitrogen gas was purged through the solution for 5 minutes. The test item was spiked to the solutions at a target concentration of 2 mg/L using a spiking solution in acetonitrile. For each sampling time, duplicate sterile vessels under vacuum were filled with 6 mL test solution and placed in
the dark in a temperature controlled environment at 50.0°C.
The spiking volume was < 1% of the sample volume. Nominal concentrations were not corrected for the spiking volume.
The concentration of the test item in the test samples was determined immediately after preparation (t=0) and after 2.4 hours and 5 days. The samples taken after 2.4 hours and 5 days were cooled to room temperature using running tap water.
Analysis was performed on subsamples of 500 μL. The samples were diluted in a 1:1 (v:v) ratio with 1% ortho-phosphoric acid in acetonitrile and analyzed.
Blank buffer solutions containing a similar content of blank spiking solution were treated similarly as the test samples and analyzed at t=0.
The pH of each of the test solutions (except for the blanks) was determined at each sampling time.

Duration:

5 d

pH:

4

Temp.:

25 °C

Initial conc. measured:

>= 0.1 - <= 100 mg/L

Duration:

5 d

pH:

7

Temp.:

25 °C

Initial conc. measured:

>= 0.1 - <= 100 mg/L

Duration:

5 d

pH:

9

Temp.:

25 °C

Initial conc. measured:

>= 0.1 - <= 100 mg/L

Number of replicates:

Buffer pH 4 and Buffer pH 9: 2
Buffer pH 7: 5

Positive controls:

no

Negative controls:

no

Transformation products:

not specified

% Recovery:

4.5

St. dev.:

0

pH:

4

Temp.:

23 °C

Duration:

5 d

% Recovery:

2.6

St. dev.:

0

pH:

7

Temp.:

23 °C

Duration:

5 d

% Recovery:

1.5

St. dev.:

0

pH:

9

Temp.:

23 °C

Duration:

5 d

Key result

pH:

4

Temp.:

25 °C

Type:

not specified

Remarks on result:

hydrolytically stable based on preliminary test

Key result

pH:

7

Temp.:

25 °C

Type:

not specified

Remarks on result:

hydrolytically stable based on preliminary test

Key result

pH:

9

Temp.:

25 °C

Type:

not specified

Remarks on result:

hydrolytically stable based on preliminary test

Validity criteria fulfilled:

yes

Conclusions:

The preliminary test (Tier 1) was performed for the determination of the rate of hydrolysis of VALSARTAN/DS at pH values normally found in the environment (pH 4-9).
At each pH value a degree of hydrolysis of < 10% was observed after 5 days. According to the guideline, performance of the main study (Tier 2) was not required.

Description of key information

No hydrolysis.

The half-life times of Valsartan at pH 4.0, pH 7.0 and pH 9.0 were estimated to be longer than one year at 25 °C (tv. (25 °C) > 1 year) in both studies.

Key value for chemical safety assessment

Half-life for hydrolysis:

1 yr

at the temperature of:

25 °C

Additional information

The results showed no significant degradation of CGP 48933 Step 9. Because less than 10 % of the hydrolysis reaction was observed after 5 days at pH 4.0, pH 7.0 and pH 9.0 respectively, CGP 48933 Step 9 was considered to be hydrolytically stable. Therefore no further testing was necessary at these pH values.