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Hydrolysis

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Reference
Endpoint:
hydrolysis
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
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
GLP compliance:
yes (incl. certificate)
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: MH-12/2014 (China)
- Expiration date of the lot/batch: 13 November 2019

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Frozen in the dark
Radiolabelling:
no
Analytical monitoring:
yes
Details on sampling:
The sample solutions were taken from the waterbath at various times and the pH of each solution recorded. The concentration of the sample solution was determined by high performance liquid chromatography (HPLC).
Buffers:
The test system used sterile buffer solutions at pH’s 4, 7 and 9.
Details on test conditions:
Performance of the Test
Preparation of the Test Solutions
Sample solutions were prepared in stoppered glass flasks at a nominal concentration of 7 g/L (Preliminary Test), or 1 g/L (Tier 2) in the relevant buffer solutions. The concentration of each solution did not exceed the lesser of 0.01 mol/L or half the water solubility. The test solutions were split into individual vessels for each data point. The solutions were shielded from light whilst maintained at the test temperature.

Preliminary Test
Sample solutions were prepared at a nominal concentration of 7 g/L at pH 4, 7 and 9 and maintained at 50.0 ± 0.5 °C for a period of 120 hours.

Tier 2
Results from the Preliminary Test showed it was necessary to undertake further testing at pH 7, with solutions (prepared at a nominal concentration of 1 g/L) being maintained at 40.0 ± 0.5 °C, 50.0 ± 0.5 °C and 60.0 ± 0.5 °C for a period of 24, 3.5 and 1.75 hours respectively, further testing at pH 9, with solutions being maintained at 10.0 ± 0.5 °C, 20.0 ± 0.5 °C and 30.0 ± 0.5 °C for a period of 24, 3.5 and 1 hours respectively.

Calculation
The response factors of the standard peak areas (unit peak area per mg/L) were calculated using the following equation.

RF = Rstd / Cstd

where:
RF = response factor for the standard solution
RSTD = peak area for the standard solution
CSTD = concentration for the standard solution (mg/L)

The sample solution (g/L) was calculated using the following equation.

C = (Rspl / RFstd) x (D / 1.00E+03)

where:
C = sample solution concentration (g/L)
RSPL = mean peak area for the sample solution
RFSTD = mean response factor for the standard solutions (unit peak area per mg/L)
D = dilution factor (10)

Calculation of the Degree of Hydrolysis
The decrease in concentration (preliminary test) or the degree of hydrolysis was calculated using the following equation:

Degree of hydrolysis in % = [ (C0 - Ct) / C0 ] · 100

where:
C0 = concentration of time 0
Ct = concentration of time t

Testing the Reaction for Pseudo First Order
The general rate expression for a first order reaction is:

d(c) / dt = - k · c

or in the integrated form

-1n (C0 - Ct) = -k · t

or

ln ct = (-k) · t – ln c0
(equation of a linear function)

Therefore, the rate constant k is the slope of a plot of ln ct versus t. The data were plotted as ln ct versus t. The linear plots prove that the hydrolysis reaction is pseudo first order. The reaction rate constant k can be calculated by regression analysis or the following equation.

-k = (1 / t) · 1n (C0 / Ct)

The half-life was calculated from the following equation:

t½ = 0.693/k

where:
c0 = Concentration of the test solution at time 0 [µg/mL]
ct = Concentration of the test solution at time t [µg/mL]
k = First order rate constant [hours-1]
t1/2 = Half-life [hours]

Evaluation of k at 25 °C
When the rate constants are known for two temperatures the rate constants at other temperatures can be calculated using the Arrhenius equation:

k = A ·e-(E / R·T)

or

1n k = -(E / R) ·1 / T) + 1n A

A plot of ln k versus 1/T gives a straight line with a slope of -E/R.

where:
k = Rate constant, measured at different temperatures
E = Activation energy [kJ/mol]
T = Absolute temperature [K]
R = Gas constant [8.314 J/mol K]
A = Pre-exponential factor

The half-life at 25 °C was interpolated/extrapolated directly from the graph.
Duration:
120 h
Temp.:
50 °C
Initial conc. measured:
7 g/L
Duration:
24 h
pH:
7
Temp.:
40 °C
Initial conc. measured:
1 g/L
Duration:
3.5 h
pH:
7
Temp.:
50 °C
Initial conc. measured:
1 g/L
Duration:
1.75 h
pH:
7
Temp.:
60 °C
Initial conc. measured:
1 g/L
Duration:
24 h
pH:
9
Initial conc. measured:
1 g/L
Duration:
3.5 h
pH:
9
Initial conc. measured:
1 g/L
Duration:
1 h
pH:
9
Initial conc. measured:
1 g/L
Number of replicates:
Two
Positive controls:
no
Negative controls:
no
Statistical methods:
No data
Preliminary study:
Preliminary pH 4 Test at 50.0 ± 0.5 ºC
Less than 10 % hydrolysis after 5 days at 50.0 ± 0.5 °C, equivalent to a half-life greater than 1 year at 25 °C.

Preliminary pH 7 Test at 50.0 ± 0.5 ºC
During the Preliminary test at pH 7 (50.0 ± 0.5 °C) there was an instability of pH causing the pH to drop to approximately pH 4, providing a plateau in the hydrolysis results. The Tier 2 test was carried out at a lower concentration with a higher buffer concentration to reduce this effect. The extent of hydrolysis after 120 hours indicated that further tests (Tier 2), conducted at 40 ± 0.5 °C, 50 ± 0.5 °C and 60 ± 0.5 °C, were required to estimate the rate constant and half-life at 25 °C.

Preliminary pH 9 Test at 50.0 ± 0.5 ºC
During the Preliminary test at pH 9 (50.0 ± 0.5 °C) there was an instability of pH causing the pH to drop to approximately pH 4, providing a plateau in the hydrolysis results. The Tier 2 test was carried out at a lower concentration with a higher buffer concentration to reduce this effect. The extent of hydrolysis after 120 hours indicated that further tests (Tier 2), conducted at 10 ± 0.5 °C, 20 ± 0.5 °C and 30 ± 0.5 °C, were required to estimate the rate constant and half-life at 25 °C.
Transformation products:
not measured
Details on hydrolysis and appearance of transformation product(s):
None
pH:
4
Temp.:
25 °C
DT50:
> 1 yr
pH:
7
Temp.:
25 °C
Hydrolysis rate constant:
0 s-1
DT50:
44.4 h
pH:
9
Temp.:
25 °C
Hydrolysis rate constant:
0 s-1
DT50:
0.934 h
Details on results:
pH 7 Test at 40.0 ± 0.5 ºC - Tier 2
N.B. The 24 hour samples indicated less than 10 % hydrolysis and are therefore not included in the statistics.

Slope = -5.17E-02
kobs = 0.119 hour-1
= 3.30E-05 second-1
t½ = 5.83 hours

pH 7 Test at 50.0 ± 0.5 ºC - Tier 2
Slope = -0.186
kobs = 0.429 hour-1
= 1.19E-04 second-1
t½ = 1.62 hours

pH 7 Test at 60.0 ± 0.5 ºC - Tier 2
Slope = -0.588
kobs = 1.36 hour-1
= 3.76E-04 second-1
t½ = 0.512 hours

pH 9 Test at 10.0 ± 0.5 ºC - Tier 2
Slope = -3.90E-02
kobs = 8.99E-02 hour-1
= 2.50E-05 second-1
t½ = 7.71 hours

pH 9 Test at 20.0 ± 0.5 ºC - Tier 2
Slope = -0.165
kobs = 0.381 hour-1
= 1.06E-04 second-1
t½ = 1.82 hours

pH 9 Test at 30.0 ± 0.5 ºC - Tier 2
Slope = -0.618
kobs = 1.42 hour-1
= 3.95E-04 second-1
t½ = 0.487 hours

pH 7 Arrhenius Data
From the graph of the data, the rate constant and half-life at 25 °C have been estimated to be as follows:
kobs = 1.56E-02 hour-1
= 4.34E-06 second-1
t½ = 44.4 hours
= 1.85 days

pH 9 Arrhenius Data
From the graph of the data, the rate constant and half-life at 25 °C have been estimated to be as follows:
kobs = 0.742 hour-1
= 2.06E-04 second-1
t½ = 0.934 hours

Tier 2

The mean peak areas relating to the standard and sample solutions are shown in the following tables:

pH 7 - 40.0 ± 0.5 °C Tier 2 Testing

Solution

Mean Peak Area

Standard 102 mg/L

1.3654 x 107

Standard 107 mg/L

1.4406 x 107

Initial Sample A, pH 7

1.3780 x 107

Initial Sample B, pH 7

1.3749 x 107

2.0 Hour Sample A, pH 7

1.0907 x 107

2.0 Hour Sample B, pH 7

1.1013 x 107

2.5 Hour Sample A, pH 7

1.0396 x 107

2.5 Hour Sample B, pH 7

1.0101 x 107

3.0 Hour Sample A, pH 7

9.7303 x 106

3.0 Hour Sample B, pH 7

9.7217 x 106

3.5 Hour Sample A, pH 7

7.0607 x 106

3.5 Hour Sample B, pH 7

9.1666 x 106

4.0 Hour Sample A, pH 7

8.6521 x 106

4.0 Hour Sample B, pH 7

8.5190 x 106

5.0 Hour Sample A, pH 7

7.6421 x 106

5.0 Hour Sample B, pH 7

7.7125 x 106

6.0 Hour Sample A, pH 7

6.7872 x 106

6.0 Hour Sample B, pH 7

6.8221 x 106

Standard 104 mg/L

1.4074 x 107

Standard 104 mg/L

1.3432 x 107

24.0 Hour Sample A, pH 7

9.6379 x 105

24.0 Hour Sample B, pH 7

9.4856 x 105

 

pH 7 - 50.0 ± 0.5 °C Tier 2 Testing

Solution

Mean Peak Area

Standard 103 mg/L

1.3881 x 107

Standard 102 mg/L

1.3744 x 107

Initial Sample A, pH 7

1.4167 x 107

0.5 Hour Sample A, pH 7

1.1660 x 107

1.0 Hour Sample A, pH 7

9.1570 x 106

1.5 Hour Sample A, pH 7

7.7388 x 106

2.0 Hour Sample A, pH 7

6.0489 x 106

2.5 Hour Sample A, pH 7

4.2968 x 106

3.0 Hour Sample A, pH 7

4.0360 x 106

3.5 Hour Sample A, pH 7

3.1537 x 106

Standard 103 mg/L

1.3858 x 107

Standard 102 mg/L

1.3703 x 107

Initial Sample B, pH 7

1.4072 x 107

0.5 Hour Sample B, pH 7

1.1129 x 107

1.0 Hour Sample B, pH 7

8.9992 x 106

1.5 Hour Sample B, pH 7

7.0426 x 106

2.0 Hour Sample B, pH 7

5.7150 x 106

2.5 Hour Sample B, pH 7

4.8178 x 106

3.0 Hour Sample B, pH 7

3.9012 x 106

3.5 Hour Sample B, pH 7

3.1857 x 106

pH 7 - 60.0 ± 0.5 °C Tier 2 Testing

Solution

Mean Peak Area

Standard 105 mg/L

1.4335 x 107

Standard 105 mg/L

1.4499 x 107

Initial Sample A, pH 7

1.3923 x 107

Initial Sample B, pH 7

1.4030 x 107

0.25 Hour Sample A, pH 7

1.0042 x 107

0.25 Hour Sample B, pH 7

1.0084 x 107

0.5 Hour Sample A, pH 7

7.4774 x 106

0.5 Hour Sample B, pH 7

7.2293 x 106

0.75 Hour Sample A, pH 7

4.9115 x 106

0.75 Hour Sample B, pH 7

5.0567 x 106

1.00 Hour Sample A, pH 7

3.6499 x 106

1.00 Hour Sample B, pH 7

3.7387 x 106

1.25 Hour Sample A, pH 7

2.6039 x 106

1.25 Hour Sample B, pH 7

2.9199 x 106

1.5 Hour Sample A, pH 7

1.7630 x 106

1.5 Hour Sample B, pH 7

1.7165 x 106

1.75 Hour Sample A, pH 7

1.3658 x 106

1.75 Hour Sample B, pH 7

1.3066 x 106

 

pH 9 - 10.0 ± 0.5 °C Tier 2 Testing

Solution

Mean Peak Area

Standard 103 mg/L

1.3020 x 107

Standard 104 mg/L

1.4321 x 107

Initial Sample A, pH 9

1.3392 x 107

Initial Sample B, pH 9

1.2491 x 107

1.0 Hour Sample A, pH 9

1.1666 x 107

1.0 Hour Sample B, pH 9

1.2046 x 107

2.0 Hour Sample A, pH 9

1.0612 x 107

2.0 Hour Sample B, pH 9

1.0766 x 107

3.0 Hour Sample A, pH 9

9.7681 x 106

3.0 Hour Sample B, pH 9

9.7669 x 106

4.0 Hour Sample A, pH 9

8.9954 x 106

4.0 Hour Sample B, pH 9

8.6560 x 106

5.0 Hour Sample A, pH 9

7.8111 x 106

5.0 Hour Sample B, pH 9

8.1407 x 106

6.0 Hour Sample A, pH 9

7.2337 x 106

6.0 Hour Sample B, pH 9

7.4981 x 106

Standard 105 mg/L

1.4363 x 107

Standard 102 mg/L

1.3937 x 107

24.0 Hour Sample A, pH 9

1.5277 x 106

24.0 Hour Sample B, pH 9

1.5452 x 106

 

pH 9 - 20.0 ± 0.5 °C Tier 2 Testing

Solution

Mean Peak Area

Standard 103 mg/L

1.3020 x 107

Standard 104 mg/L

1.4321 x 107

Initial Sample A, pH 9

1.3392 x 107

Initial Sample B, pH 9

1.2491 x 107

0.5 Hour Sample A, pH 9

1.1032 x 107

0.5 Hour Sample B, pH 9

1.0868 x 107

1.0 Hour Sample A, pH 9

8.7474 x 106

1.0 Hour Sample B, pH 9

8.8671 x 106

1.5 Hour Sample A, pH 9

7.5113 x 106

1.5 Hour Sample B, pH 9

7.3794 x 106

2.0 Hour Sample A, pH 9

5.8502 x 106

2.0 Hour Sample B, pH 9

5.9626 x 106

2.5 Hour Sample A, pH 9

5.2187 x 106

2.5 Hour Sample B, pH 9

4.9937 x 106

3.0 Hour Sample A, pH 9

4.0597 x 106

3.0 Hour Sample B, pH 9

4.0501 x 106

3.5 Hour Sample A, pH 9

3.4949 x 106

3.5 Hour Sample B, pH 9

3.4925 x 106

 

pH 9 - 30.0 ± 0.5 °C Tier 2 Testing

Solution

Mean Peak Area

Standard 101 mg/L

1.3498 x 107

Standard 104 mg/L

1.3912 x 107

Initial Sample A, pH 9

1.0594 x 107

Initial Sample B, pH 9

1.0458 x 106

0.08 Hour Sample A, pH 9

9.5097 x 106

0.08 Hour Sample B, pH 9

9.1754 x 106

0.17 Hour Sample A, pH 9

7.1215 x 106

0.17 Hour Sample B, pH 9

8.4110 x 106

0.25 Hour Sample A, pH 9

7.4856 x 106

0.25 Hour Sample B, pH 9

7.3957 x 106

0.33 Hour Sample A, pH 9

6.5182 x 106

0.33 Hour Sample B, pH 9

5.8680 x 106

0.42 Hour Sample A, pH 9

5.6080 x 106

0.42 Hour Sample B, pH 9

5.7774 x 106

0.50 Hour Sample A, pH 9

5.1638 x 106

0.50 Hour Sample B, pH 9

4.8960 x 106

0.75 Hour Sample A, pH 9

3.6562 x 106

0.75 Hour Sample B, pH 9

3.5909 x 106

1.00 Hour Sample A, pH 9

2.5133 x 106

1.00 Hour Sample B, pH 9

2.4386 x 106

 

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

pH 7 Test at 40.0 ± 0.5 ºC - Tier 2

Time (Hours)

Concentration (g/L)

Log10
concentration (g/L)

% mean initial concentration

0 (A)

1.02

7.88 x 10-3

-

0 (B)

1.02

6.92 x 10-3

-

2.0 (A)

0.806

-9.37 x 10-2

79.2

2.0 (B)

0.814

-8.94 x 10-2

80.0

2.5 (A)

0.768

-0.114

75.5

2.5 (B)

0.746

-0.127

73.4

3.0 (A)

0.719

-0.143

70.7

3.0 (B)

0.718

-0.144

70.6

3.5 (A)

0.522

-0.283

51.3

3.5 (B)

0.677

-0.169

66.6

4.0 (A)

0.639

-0.194

62.9

4.0 (B)

0.630

-0.201

61.9

5.0 (A)

0.565

-0.248

55.5

5.0 (B)

0.570

-0.244

56.0

6.0 (A)

0.502

-0.300

49.3

6.0 (B)

0.504

-0.297

49.6

24.0 (A)

7.30 x 10-2

-1.14

7.18

24.0 (B)

7.19 x 10-2

-1.14

7.07

pH 7 Test at 50.0 ± 0.5 ºC - Tier 2

Time (Hours)

Concentration (g/L)

Log10
concentration (g/L)

% mean initial concentration

0 (A)

1.05

2.13 x 10-2

-

0 (B)

1.05

1.94 x 10-2

-

0.5 (A)

0.864

-6.33 x 10-2

82.5

0.5 (B)

0.827

-8.25 x 10-2

78.9

1.0 (A)

0.679

-0.168

64.8

1.0 (B)

0.669

-0.175

63.8

1.5 (A)

0.574

-0.241

54.7

1.5 (B)

0.523

-0.281

49.9

2.0 (A)

0.448

-0.348

42.8

2.0 (B)

0.425

-0.372

40.5

2.5 (A)

0.319

-0.497

30.4

2.5 (B)

0.358

-0.446

34.2

3.0 (A)

0.299

-0.524

28.6

3.0 (B)

0.290

-0.538

27.7

3.5 (A)

0.234

-0.631

22.3

3.5 (B)

0.237

-0.626

Validity criteria fulfilled:
yes
Conclusions:
The estimated rate constant and half-lives at 25 °C of the test item are:
At pH 4 the estimated half-life at 25 °C was >1 year.
At pH 7 the estimated rate constant was 4.34E-06 s-1 at 25 °C with an estimated half-life of 44.4 hours.
At pH 9 the estimated rate constant was 2.06E-04 s-1 at 25 °C with an estimated half-life of 0.934 hours.
Executive summary:

The hydrolysis behavior as a function of pH of FAT 40069/DTE has been evaluated according to OECD Guideline 111 and EU Method C.7.

During the Preliminary test at pH 7 (50.0 ± 0.5 °C) there was an instability of pH causing the pH to drop to approximately pH 4, providing a plateau in the hydrolysis results. The Tier 2 test was carried out at a lower concentration with a higher buffer concentration to reduce this effect. The extent of hydrolysis after 120 hours indicated that further tests (Tier 2), conducted at 40 ± 0.5°C, 50 ± 0.5°C and 60 ± 0.5 °C, were required to estimate the rate constant and half-life at 25 °C. The results are summarized below:

pH

Estimated rate constant (s-1) at 25 °C

Estimated half-life at 25 °C

4

-

>1 year

7

4.34 x 10-6

44.4 hours

9

2.06 x 10-4

0.934 hours

 

 

Description of key information

The test substance FAT 40069 has been determined to be hydrolytically stable, i.e. a half-life of greater than 1 year at 25 °C at pH 4, 44.4 hours at pH 7 and 0.934 hours at pH 9.

Key value for chemical safety assessment

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

Additional information

The hydrolysis behaviour as a function of pH of test substance FAT 40069/DTE has been evaluated according to OECD Guideline 111 and EU Method C.7. During the Preliminary test at pH 7 (50.0 ± 0.5 °C) there was an instability of pH causing the pH to drop to approximately pH 4, providing a plateau in the hydrolysis results. The Tier 2 test was carried out at a lower concentration with a higher buffer concentration to reduce this effect. The extent of hydrolysis after 120 hours indicated that further tests (Tier 2), conducted at 40 ± 0.5 °C, 50 ± 0.5 °C and 60 ± 0.5 °C, were required to estimate the rate constant and half-life at 25 °C.

The results are summarized below:

pH

Estimated rate constant (s-1) at 25 °C

Estimated half-life at 25 °C

4

-

>1 year

7

4.34 x 10-6

44.4 hours

9

2.06 x 10-4

0.934 hours