2-Oxepanone, polymer with 1,4-butanediol

Hydrolysis

Link to relevant study record(s)

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

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 (t_0.5) of the reaction at pH 9, 50 °C is then given by:

t_0.5 = 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.

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.