(3AS,4S,6AR)-4-METHOXYTETRAHYDROFURO[3,4- B]FURAN-2(3H)-ONE

Hydrolysis

Link to relevant study record(s)

Reference

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2006-05-17 to 2006-07-21

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 111 (Hydrolysis as a Function of pH)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method C.7 (Degradation: Abiotic Degradation: Hydrolysis as a Function of pH)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

Identity: TIC2782 (T002907)
Batch: 00467090 (= charge 05C0836)
Purity: 99.9 %
Appearance: Solid/white
Molecular weight: 158.15 g/mol
Expiration date: May 04, 2006
Storage: At room temperature at about 20°C

Radiolabelling:

no

Analytical monitoring:

yes

Details on sampling:

- Sampling preparation: Before and after incubation, 1 mL aliquots of the test solutions at each pH value were diluted with acetone to obtain 5 mL and filtred (0.2 µm).
- Sampling intervals for the parent/transformation products: Aliquots of each test solution (10 µL) were analysed at the beginning, after 2.4 h and after 120 h.
- Sampling intervals/times for pH measurements: not reported
- Sampling intervals/times for sterility check: not reported
- Sample storage conditions before analysis: not reported

Buffers:

- pH: 4, 7, 9
- Type of buffer:
* pH 4: component: biphthalate
* pH 7: component: phosphate
* pH 9: component: borate
- Buffer solutions were sterilized for 25 min in an autoclave prior to first use.
- Nitrogen was passed through the buffer solutions for at least 5 minutes.

Estimation method (if used):

- reaction rate constant are calculated using the Arrhenius equation
- half-life time determined using the slope

Details on test conditions:

TEST SYSTEM
- Type, material and volume of test flasks, other equipment used: 50-mL glass Erlenmeyer flasks stoppered or sealed with inert material (e.g glass), fillvolume 50 mL
- Sterilisation method: glassware rinsed with sterile buffer, buffer solutions autoclaved for 25 minutes, test solutions filtered at 0.2 µm
- Lighting: not reported
- Measures to exclude oxygen: nitrogen passed through buffer solutions for 5 min to reduce the oxygen in the solution.

TEST MEDIUM
- Volume used/treatment: 50 mL
- Preparation of test medium: An amount of T002907 was dissolved in 100 ml buffer solution (pH 4, 7 or 9) to prepare a test solution. 2 aliquots of this test solution of approx. 50 ml each were transferred into 50 ml flasks in order to perform a duplicate test. To reduce the oxygen in solution, nitrogen was passed through for 5 min.

Duration:

385.6 h

pH:

4

Temp.:

50 °C

Initial conc. measured:

>= 446 - <= 611.2 other: µg/ml

Duration:

573.9 h

pH:

4

Temp.:

70 °C

Initial conc. measured:

>= 482.7 - <= 515.7 other: µg/ml

Duration:

135.9 h

pH:

4

Temp.:

80 °C

Initial conc. measured:

>= 424.9 - <= 428 other: µg/ml

Duration:

460.7 h

pH:

7

Temp.:

50 °C

Initial conc. measured:

>= 389.8 - <= 451.6 other: µg/mL

Duration:

71.1 h

pH:

7

Temp.:

70 °C

Initial conc. measured:

>= 441.4 - <= 703.4 other: µg/mL

Duration:

47.9 h

pH:

7

Temp.:

80 °C

Initial conc. measured:

>= 306.4 - <= 359.3 other: µg/mL

Duration:

459.5 h

pH:

9

Temp.:

50 °C

Initial conc. measured:

>= 393.8 - <= 463.4 other: µg/ml

Duration:

571.6 h

pH:

9

Temp.:

70 °C

Initial conc. measured:

>= 535.1 - <= 537.2 other: µg/ml

Duration:

432 h

pH:

9

Temp.:

80 °C

Initial conc. measured:

>= 388.2 - <= 536.8 other: µg/ml

Number of replicates:

2

Positive controls:

no

Negative controls:

no

Statistical methods:

not specified

Preliminary study:

A preliminary study was performed at 50°C ± 1 °C at each of pH 4, 7 and 9 in duplicate. Results are as follows:

pH 4*
- 0 hours: initial concentration measured: 132.62 and 125.42 µg/ml
- 2.4 hours: concentration measured: 120.11 and 114.67 µg/ml (corresponding to a hydrolysis rate of 9 and 9%)
- 5 days: concentration measured: 87.16 and 89.63 µg/ml (corresponding to a hydrolysis rate of 34 and 29%)
The half-life time of TIC2782 (T002907) at 50.0°C and pH 4.0 was calculated to be 2188 hours (= 91 days).

pH 7*
- 0 hours: initial concentration measured: 197.66 and 171.86 µg/ml
- 2.4 hours: concentration measured: 183.76 and 202.28 µg/ml (corresponding to a hydrolysis rate of 7 and 0%)
- 5 days: concentration measured: 142.60 and 154.79 µg/ml (corresponding to a hydrolysis rate of 28 and 23%)
The half-life time of TIC2782 (T002907) at 50.0°C and pH 7.0 was calculated to be 415 hours (= 17 days).

pH 9*
- 0 hours: initial concentration measured: 158.06 and 124.62 µg/ml
- 2.4 hours: concentration measured: 133.33 and 85.38 µg/ml (corresponding to a hydrolysis rate of 16 and 31%)
- 5 days: concentration measured: 102.48 and 77.70 µg/mL (corresponding to a hydrolysis rate of 35 and 38%)
The half-life time of TIC2782 (T002907) at 50.0°C and pH 9.0 was calculated to be 1556 hours (65 days).

Test performance:

Due to the instability of the test item found in the preliminary study at 50°C, further hydrolysis tests were performed at 70°C and 80°C in the buffered test solution at pH 4, 7 and 9.

The half-life time at pH 4.0 and 70°C was calculated to be 236 hours (10 days).
The half-life time at pH 4.0 and 80°C was calculated to be 72 hours (3 days).
The half-life time at pH 7.0 and 70°C was calculated to be 42 hours.
The half-life time at pH 7.0 and 80°C was calculated to be 22 hours.
The half-life time at pH 9.0 and 70°C was calculated to be 815 hours (34 days).
The half-life time at pH 9.0 and 80°C was calculated to be 527 hours (22 days).

Transformation products:

not specified

Details on hydrolysis and appearance of transformation product(s):

no data

pH:

4

Temp.:

25 °C

Hydrolysis rate constant:

0 h-1

DT50:

2 169 d

Type:

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

Remarks on result:

other: ln k = -(E/R)x (1/T) + ln A, slope = -12485, ln A = 30.6, coefficient of regression = -0.980

pH:

7

Temp.:

25 °C

Hydrolysis rate constant:

0 h-1

DT50:

322 d

Type:

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

Remarks on result:

other: ln k = -(E/R)x (1/T) + ln A, slope = -11484, ln A = 29.2, coefficient of regression = -0.995

pH:

9

Temp.:

25 °C

Hydrolysis rate constant:

0 h-1

DT50:

187 d

Type:

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

Remarks on result:

other: ln k = -(E/R)x (1/T) + ln A, slope = -4066, ln A = 4.9, coefficient of regression = -0.914

Details on results:

TEST CONDITIONS
- pH, sterility, temperature, and other experimental conditions maintained throughout the study: no data
- Anomalies or problems encountered (if yes): no data

MAJOR TRANSFORMATION PRODUCTS
- no data reported

MINOR TRANSFORMATION PRODUCTS
- no data reported

MINERALISATION (distinguish between dark and irradiated samples)
- no data reported

INDICATION OF UNSTABLE TRANSFORMATION PRODUCTS:
- no data reported

VOLATILIZATION (at end of study)
- no data reported

PATHWAYS OF HYDROLYSIS
- no data reported

UNIDENTIFIED RADIOACTIVITY (at end of study)
- no data reported

Validity criteria fulfilled:

yes

Conclusions:

Hydrolysis was studied for T002907 following guideline OECD 111 during 5 days at pH 4, 7 and 9 and at 50°C. During a preliminary study, T002907 was not stable at pH 4.0, pH 7.0 and pH 9.0. Further testing was performed at 50°C, 70°C and 80°C for pH 4.0, 7.0 and 9.0.
Using the Arrhenius equation, it was concluded that the estimated half-life time at 25°C is 52056 hours ( 2169 days) at pH 4.0, 7737 hours (322 days) at pH 7.0 and 4495 hours (187 days) at pH 9.0 respectively. The results of the test can be considered reliable without restriction.

Description of key information

One study (Weissenfeld, 2006) was performed according to OECD guideline 111 and regarded as a key study (Klimisch score of 1). A half-life time of 2169 days, 322 days and 187 days at 25 °C and pH 4, 7 and 9 respectively were determined for T002907.

Key value for chemical safety assessment

Half-life for hydrolysis:

7 737 h

at the temperature of:

25 °C

Additional information

The hydrolysis of the test item was performed at 50.0°C ± 0.1°C at each of pH 4.0, pH 7.0 and pH 9.0.

TIC2782 (T002907) was not stable at pH 4.0, pH 7.0 and at pH 9.0, further testing was performed at elevated temperatures (50°C, 70°C and 80°C) in order to calculate the rate constant (k25) and the half-life time of the hydrolysis at pH 4.0, pH 7.0 and pH 9.0 at 25°C. The results are summarised below (the values typed in italics were calculated using the Arrhenius equation):

TIC2782 (T002907) at pH 4.0 has a half-life time of 52056 hours (2169 days) at 25°C.

TIC2782 (T002907) at pH 7.0 has a half-life time of 7737 hours (322 days) at 25°C.

TIC2782 (T002907) at pH 9.0 has a half-life time of 4495 hours (187 days) at 25°C.