2-Oxepanone, polymer with 1,6-hexanediol

Hydrolysis

Link to relevant study record(s)

Reference

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2011

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, 76,, 150 and 172 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 2011-11-02. 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. About 20-25 ml (20-25 g) of the filtered solutions were evaporated to dryness at 80 °C over night in a heating cabinet. The residue, corresponding to the dissolved material was weighed out, results were about 55 mg, which means that only about 20-25 % (22.5% for Rep.1 and 22.5% for Rep. 2) 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 2047A indicates a linear function equated with a first order reaction rate, which means that the rate constant (kobs) for the hydrolysis of CAPA 2047A 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.

Also the decrease in concentration of the dissolved product CAPA 2047A (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. 35 h

Type:

(pseudo-)first order (= half-life)

Remarks on result:

other: The higher molecular oligomers of CAPA 2043 is not soluble in water, meaning that only the lower molecular oligomers are submitted to the hydrolysis conditions.

Details on results:

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 0-172 h after preparation, and analysed by HPLC 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	1,6 HDO (mg/L)	6-hydroxyhexanoic acid (mg/L)	oligomers (area)	% hydrolysed*
Replicate 1 -20 °C	81	<10	5.621	-
Replicate 1 50 °C	91	22	5.534	2
Replicate 2 -20 °C	71	<10	5.685	-
Replicate 2 50 °C	90	22	5.593	2

* 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	1,6 HDO (mg/L)	6-hydroxyhexanoic acid (mg/L)	oligomers (area)	% hydrolysed
Replicate 1 -20°C	89	<10	5.287	-
Replicate 1 50°C	100	32	5.072	4
Replicate 2 -20°C	87	<10	5.662	-
Replicate 2 50°C	94	34	5.459	4

Table 7. Results for pH 9.

pH 9	1,6 HDO (mg/L)	6-hydroxyhexanoic acid (mg/L)	ε-caprolactone (mg/L)	oligomers (area)	%hydrolysed
Replicate 1 -20°C	85	<10	10	5.364	-
Replicate 1 50°C	380	430	<10	0.472	91
Replicate 2 -20°C	90	<10	12	5.665	-
Replicate 2 50°C	400	460	<10	0.545	90

Table 8. Results for 1,6-HDO, Tier 2

Time (h)	1,4-BDO (mg/L)		pH
	Replicate 1	Replicate 2
0	100	98	9.1
3	120	110	-
7	160	150	-
24	240	230	-
31	270	250	-
48	280	300	-
55	330	350	-
76	340	350	-
150	410	410	-
172	400	400	8.8

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	37	40	-
7	77	76	-
24	200	210	-
31	240	240	-
48	310	310	-
55	330	330	-
76	380	390	-
150	470	470	-
172	480	480	8.8

Table 10. Results for product CAPA 2047A (oligomers), Tier 2

Time (h)	Capa 2047A				pH
	Replicate 1		Replicate 2
	area	%hydrolysis	area	%hydrolysis
0	5.686	-	5.722	-	9.1
3	5.364	6	5.400	6	-
7	4.921	14	4.931	14	-
24	3.430	40	3.383	41	-
31	3.016	47	2.965	48	-
48	2.176	62	2.102	63	-
55	1.965	65	1.890	67	-
76	1.390	76	1.308	77	-
150	0.339	94	0.360	94	-
172	0.210	96	0.242	96	8.8

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	5.364	5.4 x 10-6	5.400	5.36 x 10-6
25200	7	4.921	5.73 x 10-6	4.931	5.90 x 10-6
86400	24	3.430	5.85 x 10-6	3.383	6.08 x 10-6
111600	31	3.016	5.68 x 10-6	2.965	5.89 x 10-6
172800	48	2.176	5.56 x 10-6	2.101	5.80 x 10-6
198000	55	1.965	5.37 x 10-6	1.890	5.59 x 10-6
273600	76	1.390	5.15 x 10-6	1.308	5.39 x 10-6
540000	150	0.339	5.22 x 10-6	0.360	5.12 x 10-6
619200	172	0.210	5.33 x 10-6	0.242	5.11 x 10-6
Mean value			5.5 x 10-6		5.6 x 10-6
sd			0.2 x 10-6		0.4 x 10-6

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≈35 ± 2 h.

Validity criteria fulfilled:

yes

Conclusions:

Preliminary test (Tier 1) showed that the product CAPA 2047A can be considered stable at pH 4 and 7 (50 °C).
At pH 9 (50 °C), CAPA 2047A seemed to be hydrolysed to a high degree within 5 days. Kinetic studies gave a half-life of about 35 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 to guideline 111 using the substance CAPA 2047A. The product CAPA 2047A can be considered stable at pH 4 and 7 (50 °C). At pH 9 (50 °C), CAPA 2047A seemed to be hydrolysed to a high degree within 5 days. Kinetic studies gave a half-life of about 35 h at the given conditions for pH 9.

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 1,6-hexanediol is hydrolytically stable.

Additional information

A study was conducted to OECD guideline 111 using the substance 2-Oxepanone, polymer with 1,6-hexanediol. The substance can be considered stable at pH 4 and 7 (50 °C). At pH 9 (50 °C), 2-Oxepanone, polymer with 1,6-hexanediol seemed to be hydrolysed to a high degree within 5 days. Kinetic studies gave a half-life of about 35 h at the given conditions for pH 9.