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Hydrolysis

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Reference
Endpoint:
hydrolysis
Type of information:
experimental study
Adequacy of study:
key study
Study period:
07 June 2018 to 10 July 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Study was conducted in accordance with international guidelines and in accordance with GLP
Qualifier:
according to
Guideline:
OECD Guideline 111 (Hydrolysis as a Function of pH)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method C.7 (Degradation: Abiotic Degradation: Hydrolysis as a Function of pH)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 835.2120 (Hydrolysis of Parent and Degradates as a Function of pH at 25°C)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
Date of Inspection: 18 July 2017 - 20 July 2017 Date on Certfiicate: 28 November 2017
Radiolabelling:
no
Analytical monitoring:
yes
Details on sampling:
- Sampling intervals for the parent/transformation products: 24 and 120 hours
- Sampling intervals/times for pH measurements: 24 and 120 hours
Buffers:
- pH: 4.0, 7.0 and 9.0
- Composition of buffer:
pH 4.0: Components - citric acid (0.06 mol dm-3), sodium chloride (0.04 mol dm-3), sodium hydroxide (0.07 mol dm-3)
pH 7.0: Components - disodium hydrogen orthophoshate (0.03 mol dm-3), potassium hydrogogen orthophosphate (0.02 mol dm-3), sodium chloride (0.02 mol dm-3)
pH 9.0: Components - disodium tetraborate (0.01 mol dm-3), sodium chloride (0.02 mol dm-3)

The buffer solutions were passed through a 0.2 μm membrane filter to sterilise and subjected to ultrasonication and degassing with nitrogen to minimise dissolved oxygen.
Details on test conditions:
TEST SYSTEM
- Type, material and volume of test flasks, other equipment used: Sealed glass vessels with minimal headspace
- Lighting: N/A - sample solutions were shielded from light
- Measures taken to avoid photolytic effects: As above - sample solutions were shieded from light and for analysis were transferred to amber vials
- Measures to exclude oxygen: Vessels are sealed and the buffer solutions were passed through a 0.2 μm membrane filter to sterilise and subjected to ultrasonication and degassing with nitrogen to minimise dissolved oxygen.
- Temperature: 50.0 ± 0.5 °C

Duration:
120 h
pH:
4
Temp.:
50 °C
Initial conc. measured:
73.9 mg/L
Duration:
120 h
pH:
7
Temp.:
50 °C
Initial conc. measured:
72.9 mg/L
Duration:
120 h
pH:
9
Temp.:
50 °C
Initial conc. measured:
74.1 mg/L
Number of replicates:
2
Positive controls:
no
Negative controls:
yes
Preliminary study:
The test item was determined to be hydrolytically stable therefore only a preliminary study is required. Results for the preliminary study are presented below.
Transformation products:
not specified
% Recovery:
98.2
pH:
4
Temp.:
50 °C
Duration:
120 h
% Recovery:
99.3
pH:
7
Temp.:
50 °C
Duration:
120 h
% Recovery:
97.7
pH:
9
Temp.:
50 °C
Duration:
120 h
Key result
pH:
4
Temp.:
25 °C
DT50:
> 1 yr
Key result
pH:
7
Temp.:
25 °C
DT50:
> 1 yr
Key result
pH:
9
Temp.:
25 °C
DT50:
> 1 yr
Details on results:
TEST CONDITIONS
- pH, sterility, temperature, and other experimental conditions maintained throughout the study: Yes

The mean peak areas relating to the standard and sample solutions for the initial time, 24 hour and 120 hour time points for pH 4, 7 and 9 are shown in the following tables:

Table 1 Initial

Solution

Mean peak area

Standard pH 4, 70.8 mg/L

4.8004 x 107

Standard pH 4, 70.5 mg/L

5.1345 x 107

Sample A pH 4, initial

2.5940 x 107

Sample B pH 4, initial

2.6013 x 107

Standard pH 7, 70.8 mg/L

5.0283 x 107

Standard pH 7, 70.5 mg/L

5.1186 x 107

Sample A pH 7, initial

2.6223 x 107

Sample B pH 7, initial

2.6097 x 107

Standard pH 9, 70.8 mg/L

4.9184 x 107

Standard pH 9, 70.5 mg/L

5.0771 x 107

Sample A pH 9, initial

2.6244 x 107

Sample B pH 9, initial

2.6194 x 107

Table 2 24 Hour*

*Note: standard response replication, see Discussion of Standard 71.1 mg/L

Solution

Mean peak area

Standard pH 4, 70.9 mg/L

4.9976 x 107

Standard pH 4, 71.1 mg/L

4.5112 x 107

Sample A pH 4, 24-hour

2.6075 x 107

Sample B pH 4, 24-hour

2.5615 x 107

Standard pH 7, 70.9 mg/L

5.0858 x 107

Standard pH 7, 71.1 mg/L

4.4549 x 107

Sample A pH 7, 24-hour

2.5906 x 107

Sample B pH 7, 24-hour

2.5876 x 107

Standard pH 9, 70.9 mg/L

5.0134 x 107

Standard pH 9, 71.1 mg/L

4.4712 x 107

Sample A pH 9, 24-hour

2.5943 x 107

Sample B pH 9, 24-hour

2.6012 x 107

Table 3 120 Hour

Solution

Mean peak area

Standard pH 4, 70.8 mg/L

5.0926 x 107

Standard pH 4, 70.6 mg/L

5.0458 x 107

Sample A pH 4, 24-hour

2.5978 x 107

Sample B pH 4, 24-hour

2.6015 x 107

Standard pH 7, 70.8 mg/L

5.0794 x 107

Standard pH 7, 70.6 mg/L

5.1180 x 107

Sample A pH 7, 24-hour

2.6336 x 107

Sample B pH 7, 24-hour

2.5907 x 107

Standard pH 9, 70.8 mg/L

5.1368 x 107

Standard pH 9, 70.6 mg/L

5.0602 x 107

Sample A pH 9, 24-hour

2.6095 x 107

Sample B pH 9, 24-hour

2.6113 x 107

The test item concentrations at the given time points are shown in the following tables:

Table 4 - pH 4 at 50.0 ± 0.5 °C

Time (hours)

Concentration (mg/L)

Percentage of mean initial concentration

A

B

A

B

0

73.8

74.0

-

-

24

77.8

76.5

105

104

120

72.4

72.5

98.1

98.2

Less than 10% hydrolysis after 5 days at 50 °C, equivalent to half-life > 1 year at 25°C.

Table 5 - pH 7 at 50.0 ± 0.5 °C

Time (hours)

Concentration (mg/L)

Percentage of mean initial concentration

A

B

A

B

0

73.0

72.7

-

-

24

77.1

77.0

106

106

120

73.0

71.8

100

98.6

Less than 10% hydrolysis after 5 days at 50 °C, equivalent to half-life > 1 year at 25°C.

Table 6 - pH 9 at 50.0 ± 0.5 °C

Time (hours)

Concentration (mg/L)

Percentage of mean initial concentration

A

B

A

B

0

74.2

74.0

-

-

24

77.7

77.9

105

105

120

72.4

72.4

97.6

97.7

Less than 10% hydrolysis after 5 days at 50 °C, equivalent to half-life > 1 year at 25°C.

Validation

The linearity of the detector response with respect to concentration was assessed over the nominal concentration range of 2.5 to 100 mg/L. The plot was found to be 1storder with a correlation coefficient (r) of 1.000.

Discussion

The concentration of each solution did not exceed the lesser of 0.01 mol/L or half the water solubility.

No significant peaks were observed at the approximate retention time of the test item on analysis of any matrix blank solutions.

The pH of all the test solutions remained stable throughout testing (< ±0.1 pH unit) of the target pH 4, 7 and 9.

Standard solutions were prepared at approximately twice the concentration of the sample solutions in error, i.e. 70 mg/L, whereas the sample solutions were nominally 35 mg/L. The detector response was linear over the working concentration range and there was no significant effect on the study.

Standard solutions for the 24-Hour sample analysis demonstrated poor replication resulting in an increase in the measured test item concentration in the sample solutions (approximately 105% of initial concentration). Analysis of the 120-Hour sample solutions were consistent with the initial assay and demonstrated that there was no significant hydrolysis of the test item at pH 4, 7 and 9 (approximately 98% of initial concentration). Therefore, it was considered that the overall results were acceptable.

Validity criteria fulfilled:
yes
Conclusions:
The half-lives at 25 °C of the test item were estimated to be > 1 year for pH 4, 7 and 9.
Executive summary:

Assessment of hydrolytic stability was carried out using a procedure designed to be compatible with Method C.7 Abiotic Degradation, Hydrolysis as a Function of pH of Commission Regulation (EC) No 440/2008 of 30 May 2008, Method 111 of the OECD Guidelines for Testing of Chemicals, 13 April 2004 and Method 835.2120 of the OCSPP Guidelines. The results are as follows:

pH

Estimated half-life at 25°C

4

> 1 year

7

> 1 year

9

> 1 year

Description of key information

The half-lives at 25 °C of the test item were estimated to be > 1 year for pH 4, 7 and 9.

Key value for chemical safety assessment

Half-life for hydrolysis:
1 yr
at the temperature of:
25 °C

Additional information

Assessment of hydrolytic stability was carried out using a procedure designed to be compatible with Method C.7 Abiotic Degradation, Hydrolysis as a Function of pH of Commission Regulation (EC) No 440/2008 of 30 May 2008, Method 111 of the OECD Guidelines for Testing of Chemicals, 13 April 2004 and Method 835.2120 of the OCSPP Guidelines. The results are as follows:

pH

Estimated half-life at 25°C

4

> 1 year

7

> 1 year

9

> 1 year

As the minimum estimated half life, 1 year is selected as the key value for chemical safety assessment.