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Reference
Endpoint:
hydrolysis
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Non-GLP study conducted to OECD 111. However, a number of deviations from the guideline were recorded.
Qualifier:
according to
Guideline:
OECD Guideline 111 (Hydrolysis as a Function of pH)
Deviations:
yes
Remarks:
Guideline regarding temperature variation (50 ± 0.5°C) not fulfilled
Principles of method if other than guideline:
The demands of the guideline regarding sterility and temperature variation (50 ± 0.5°C) were not fulfilled (the heating cabinet instruction manual stated that the temperature should not vary more than ± 0.4°C, this was however not controlled), but considered to be of little significance to the result.
GLP compliance:
not specified
Remarks:
The demands of the guideline regarding sterility and temperature variation (50 ± 0.5°C) were not fulfilled, but considered to be of little significance to the result. See notes in the field above.
Radiolabelling:
no
Analytical monitoring:
no
Details on sampling:
Tier 1: Sampling interval for the parent/transformation products: 5 days.
Tier 2 (pH 9 only): 0, 3, 7, 24, 31, 48, 55, 72, 78, 145 and 169 hours.
Buffers:
pH 4 buffer: pH 4 ± 0.01 (20°C) (citric acid/sodium hydroxide/hydrogen chloride)
pH 7 buffer: pH 7 ± 0.01 (20°C) (di-sodium hydrogen phosphate/potassium di-hydrogen phosphate)
pH 9 buffer: pH 9 ± 0.01 (20°C) (boric acid/potassium chloride/sodium hydroxide)

All water used were of grade 1 according to EN-ISO 3696-1995.
Details on test conditions:
Tier 1, Preliminary test

Test conditions

The test was started at 2011-07-06. Duplicate samples were made for each pH.
About 500 mg of the substance was dissolved in 50 ml of water. The solubility in water, of especially the higher molecular components is very low, and the insoluble material is filtered off by passing the solution through a 0.45 μm syringe filter. 10 ml of the filtered solution is diluted in 20 ml of pH buffer. The mixture was then divided in half and stored for five days, the reference part in a freezer (-20 °C) and the other in a heating cabinet (50 °C).

GC-analysis, composition of dissolved product:

Since the insoluble higher molecular components are filtered off prior to dilution in pH buffers, high temperature GC with on-column injection was run, in order to find out the composition of the product components that actually were dissolved:

Sample preparation: As above, 500 mg/50 ml water (2 replicates), filtered. 20 ml (20 g) of the filtered solutions were evaporated to dryness at 80 °C with N2 flush. The residue, corresponding to the dissolved material was weighed out, results were about 65 mg, which means that only about 30-35 % of the 500 mg of substance dissolves in 50 ml of water, the rest is insoluble and is filtered away. The residues were analysed according to the GC-method, see under methods. Results are summarised in Table 2 (presented in section 'Any other information on materials and methods incl. tables').

To compensate for the difference in response due to the silylation a normalisation was done by dividing the area with the ratio between the molecular weight of the derivative and that of the underivatised molecule.

As expected, the water soluble part only consists of the low molecular part of the substance.

pH measurements

pH in the solutions was checked at the start and after five days. Results are summarised in Tables 3 and 4 (presented in section 'Any other information on materials and methods incl. tables').
Duration:
5 d
pH:
4
Temp.:
50 °C
Initial conc. measured:
10 g/L
Duration:
5 d
pH:
7
Temp.:
50 °C
Initial conc. measured:
10 g/L
Duration:
5 d
pH:
9
Temp.:
50 °C
Initial conc. measured:
10 g/L
Number of replicates:
Tier 1: Two replicates
Tier 2: Two replicates
Statistical methods:
The log-transformed data vs. time for CAPA 2043 indicates a linear function equated with a first order reaction rate, which means that the rate constant (kobs) for the hydrolysis of CAPA 3050 at pH 9, 50 °C is given by the expression:

kobs = (1/t) In (A0/At) (2)
Preliminary study:
HPLC- and GC-analysis

After five days the mixtures were analysed using HPLC and GC. The amount of free 6-hydroxyhexanoic acid (hydrolysis product) was quantified using external standard calibration (HPLC).

6-hydroxyhexanoic acid reference was prepared by treating ε-caprolactone with 1 M NaOH at 80 °C for 1 h.

Amount of free ε-caprolactone was quantified using external standard calibration (HPLC). ε- caprolactone is not a hydrolysis product but it exists at low levels in the product and is converted to 6-hydroxyhexanoic acid.

Amount of free 1,4-butanediol was determined by GC using internal standard calibration. However, there seemed to be quite large deviations in the results obtained from this method. But they were good enough to see a general increasing trend of the 1,4-BDO concentration, when hydrolysis was taking place.

Also the decrease in concentration of the dissolved product CAPA 2043 (oligomers) was estimated by calculating the decrease in area of a group of three peaks representing the different oligomers. All samples were allowed to reach room temperature and were then injected on the HPLC-system without dilution.

Refer to tables 5 to 7 presented in section 'Any other information on results incl. tables'.
Transformation products:
not measured
pH:
4
Temp.:
50 °C
Remarks on result:
hydrolytically stable based on preliminary test
pH:
7
Temp.:
50 °C
Remarks on result:
hydrolytically stable based on preliminary test
pH:
9
Temp.:
50 °C
DT50:
ca. 27 h
Type:
(pseudo-)first order (= half-life)
Remarks on result:
other: The higher molecular oligomers of CAPA 2043 are not soluble in water, meaning that only the lower molecular oligomers are submitted to the hydrolysis conditions.
Details on results:
Comment, pH 4: The hydrolysis calculations based on the decrease in area of oligomers are very uncertain when there is a low degree of hydrolysis taking place. However, you can also use the increase of the amount 6-hydroxyhexanoic acid, when estimating how much of the product that is hydrolysed at pH 4. Concentration of 6-hydroxyhexanoic acid at 50 °C is about 25 mg/L (Table 5).
Roughly 15 mg/L originates from converted ε-caprolactone, which means that there are about 10 mg/L 6-hydroxyhexanoic acid due to hydrolysis of the product.

In Table 7, pH 9, where most of the product was hydrolysed, about 650 mg/L 6-hydroxyhexanoic acid corresponded to about 90 % hydrolysed.

(10 mg/ml/650 mg/ml) x 90 % < 2 % hydrolysed

Comment, pH 7: About 5 % hydrolysed. See Comment, pH 4 for calculations.

Comment, pH 9: Significant increases of both 1,4-BDO and 6-hydroxyhexanoic acid concentrations indicating that the product was hydrolysed to a high degree. Decrease in area of oligomer peaks indicating %hydrolysed > 90.

Tier 2, Hydrolysis of unstable substances

The preliminary test, Tier 1, indicated hydrolysis of less than 10 % for pH 4 and pH 7. At pH 9 the product seems to be over 90 % hydrolysed after 5 days in 50 °C . Therefore, Tier 2, Hydrolysis of unstable substances, was also performed for pH 9, 50 °C.

Duplicate samples were analysed.

Preparation of solutions was done in the same way as in Tier 1, except no part of the solution was kept in a freezer (-20 °C) for reference. Samples were taken out between 0-169 h after preparation, and analysed by HPLC and GC according to the same methods as in Tier 1. pH was measured at the start and again at the end of the trial.

Refer to tables 8 to 11 presented in section 'Any other information on results incl. tables'.

Table 5. Results for pH 4.

pH 4

1,4 BDO (mg/L)

6-hydroxyhexanoic acid (mg/L)

ε-caprolactone

(mg/L)

oligomers

(area)

%hydrolysed*

Replicate 1 -20 °C

140

<10

13

7.417

-

Replicate 1 50 °C

130

26

<10

7.892

-6

Replicate 2 -20 °C

120

<10

16

8.628

-

Replicate 2 50 °C

150

26

<10

8.156

6

* The areas of 3 peaks representing oligomers (product) are summed up. Results from reference samples (-20 °C) are set to 0 = 0 %hydrolysed = no hydrolysis. The amount of hydrolysis taking place is then calculated by:

 

%hydrolysed = (1 -(Area0/Areat)) x 100 (1)

 

Area0 = area of oligomers in reference sample (-20 °C) for Tier 1, and oligomer-area for sample at t = 0 h, for Tier 2. Areat = area of oligomers in sample kept at 50 °C for Tier 1, and oligomer-area for sample at t = n h, for Tier 2.

Table 6. Results for pH 7.

pH 7

1,4 BDO (mg/L)

6-hydroxyhexanoic acid (mg/L)

ε-caprolactone

(mg/L)

oligomers

(area)

%hydrolysed

Replicate 1 -20°C

240

<10

14

6.933

-

Replicate 1 50°C

160

51

<10

7.404

-7

Replicate 2 -20°C

-

<10

14

7.297

-

Replicate 2 50°C

160

53

<10

7.636

-5

Table 7. Results for pH 9.

pH 9

1,4 BDO (mg/L)

6-hydroxyhexanoic acid (mg/L)

ε-caprolactone

(mg/L)

oligomers

(area)

%hydrolysed

Replicate 1 -20°C

200

<10

10

5.632

-

Replicate 1 50°C

360

630

<10

0.462

92

Replicate 2 -20°C

265

<10

12

6.491

-

Replicate 2 50°C

380

660

<10

0.513

92

Table 8. Results for 1,4-BDO, Tier 2

Time (h)

1,4-BDO (mg/L)

pH

Replicate 1

Replicate 2

0

210

240

9.1

3

170

210

-

7

230

240

-

24

320

300

-

31

300

270

-

48

400

360

-

55

370

360

-

72

380

370

-

78

390

360

-

145

410

390

-

169

380

430

8.7

Table 9. Results for 6-hydroxyhexanoic acid, Tier 2

Time (h)

6-hydroxyhexanoic acid (mg/L)

pH

Replicate 1

Replicate 2

0

<10

<10

9.1

3

60

57

-

7

130

120

-

24

320

320

-

31

380

370

-

48

470

460

-

55

500

480

-

72

560

530

-

78

570

550

-

145

680

660

-

169

700

680

8.7

Table 10. Results for product CAPA 2043 (oligomers), Tier 2

 

Time (h)

Capa 2043

 

pH

Replicate 1

Replicate 2

area

%hydrolysis

area

%hydrolysis

0

8.513

0

8.255

0

9.1

3

7.830

8

7.567

8

-

7

6.971

18

6.755

18

-

24

4.311

49

4.136

50

-

31

3.568

58

3.606

56

-

48

2.404

72

2.299

72

-

55

2.047

76

2.128

74

-

72

1.412

83

1.454

82

-

78

1.328

84

1.306

84

-

145

0.324

96

0.302

96

-

169

0.208

98

0.189

98

8.7

Table 11. Calculation of kobs (pH 9, 50 °C)

t (s)

t (h)

Replicate 1

Replicate 2

At

kobs(s-1)

At

kobs(s-1)

10800

3

7.830

7.74 x 10-6

8.255

8.06 x 10-6

25200

7

6.971

7.93 x 10-6

7.567

7.96 x 10-6

86400

24

4.311

7.88 x 10-6

6.755

8.00 x 10-6

111600

31

3.568

7.79 x 10-6

4.136

7.42 x 10-6

172800

48

2.404

7.32 x 10-6

3.606

7.40 x 10-6

198000

55

2.047

7.20 x 10-6

2.299

6.85 x 10-6

259200

72

1.412

6.93 x 10-6

2.128

6.70 x 10-6

280800

78

1.328

6.62 x 10-6

1.454

6.57 x 10-6

522000

145

0.324

6.26 x 10-6

1.306

6.34 x 10-6

608400

169

0.208

6.10 x 10-6

0.302

6.21 x 10-6

Mean value

7.2 x 10-6

 

7.2 x 10-6

sd

0.7 x 10-6

0.7 x 10-6

There are large deviations in the calculated Kobs-values with a clear trend: Increasing time decreasing Kobs.

 

Half-life (t0.5) of the reaction at pH 9, 50 °C is then given by:

t0.5 = In2/kobs (3)

Which gives t0.5 ≈27 ± 3 h.

Validity criteria fulfilled:
yes
Conclusions:
Preliminary test (Tier 1) showed that the product CAPA 2043 can be considered stable at pH 4 and 7 (50 °C).
At pH 9, 50 °C, CAPA 2043 seemed to be hydrolysed to a high degree within 5 days. Kinetic studies gave a half-life of about 27 h at the given conditions.
It is also worth mentioning the fact that the higher molecular oligomers of CAPA 2043 is not soluble in water, see Table 2, which means that only the lower molecular oligomers are submitted to the hydrolysis conditions.
Executive summary:

A study was conducted according to OECD guideline 111 using the substance CAPA 2043. Results showed that CAPA 2043 can be considered hydrolytically stable at pH 4 and 7 (50 °C). At pH 9, 50 °C, CAPA 2043 seemed to be hydrolysed to a high degree within 5 days. Kinetic studies gave a half-life of about 27 h at the given conditions.

Description of key information

A reliable experimental study (with acceptable restrictions) conducted according to OECD Guideline 111 is available which shows that 2-Oxepanone, polymer with 1,4-butanediol is hydrolytically stable.

Key value for chemical safety assessment

Additional information

One key study is presented. The conclusions of this study are that CAPA 2043 (2-oxepanone, polymer with 1,4-butanediol) is hydrolytically stable over the tested pH ranges. As such hydrolysis is not expected to be a relevant degradation pathway for 2-oxepanone, polymer with 1,4-butanediol.