2-Propen-1-one, 3-(dimethylamino)-1-(3-pyridinyl)-

Hydrolysis

Administrative data

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

key study

Study period:

20 July 2000 - 1 August 2000

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: This study has been performed according to OECD and EC guidelines and according to GLP principles.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2000

Report date:

2000

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

434-770-8

EC Name:

-

Cas Number:

55314-16-4

Molecular formula:

C10 H12 N2 O1

IUPAC Name:

3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one

Details on test material:

Identification: STI571 Y5A
Description: Brown solid
Batch: 0093800007
Purity: >95%
Test substance storage: In refrigerator in the dark
Stability under storage conditions: Not indicated
Expiry date: 08 May 2001

Radiolabelling:

no

Study design

Analytical monitoring:

yes

Details on sampling:

Preparation of the test solutions:
Prior to the start of each test, the test solutions were freshly prepared. Test substance amounts of approximately 80 mg were weighed into 50.0 ml volumetric flasks. The flasks were filled up to the mark with aqueous solutions buffered at pH 4, pH 7 and pH 9, respectively. The resultant solutions were filter-sterilized through a 0.2 µm membrane filter (FP 030/3, Schleicher & Schuell, 's-Hertogenbosch, The Netherlands) and transferred into sterile glass vessels. To exclude oxygen, nitrogen gas was bubbled through each solution for 5 minutes. Thereafter, each vessel was tightly sealed with a septum-crimpcap.

Preliminary test (preliminary test according to EEC Guideline C.7.):
After preparation, the test solutions at pH 4, pH 7 and pH 9 were placed in a thermostatically controlled waterbath at 50.0 ± 0.5°C in the dark. The concentration of the test substance was determined immediately after preparation (t=0) and after 2.4 hours (all test solutions) and 5 days (test solutions at pH 7 and pH 9) of incubation. At each sampling point, a 2 ml sample was taken for pretreatment and analysis.
For each test solution, the pH value of each sample was measured at room temperature.

Testing of pseudo-first order kinetics (Test 1 according to EEC guideline C.7):
During the preliminary test, significant hydrolysis (i.e. a decrease in test substance concentration at 50°C < 50% after 2.4 hours but > 10% after 5 days) was observed at pH 7 and pH 9. Therefore, Test 1 was carried out at these pH values.
After preparation, the test solutions pH 7 and pH 9 were placed in a thermostatically controlled waterbath at 70.0 ± 0.5°C in the dark. The concentration of the test substance at pH 7 was determined immediately after preparation (t=0) and 3, 4, 4.5, 6 and 7 hours after t=0. The concentration of the test substance at pH 9 was determined immediately after preparation (t=0) and 4, 4.5, 5, 6, 7 and 8 hours after t=0. At each sampling point, a 2 ml sample was taken for pretreatment and analysis.
For each test solution, the logarithms of the relative concentrations between 80% and 30% (i.e. between 20% and 70% hydrolysis) were plotted against time. Because these were straight lines, the reaction was considered to be (pseudo)-first order and Test 3 according to EEC guideline C.7 was performed. The results from Test 1 for pH 7 and pH 9 were also used for the calculation of the rate constant at 25˚C in Test 3.

Determination of the half-life time (t½) at 25°C (Test 3 according to EEC guideline C.7):
Because the resultant lines from Test 1 were straight lines for pH 7 and pH 9, Test 3 was carried out. Because Test 1 at pH 7 and pH 9 were performed at 70°C, Test 3 was performed at only one temperature > 50°C (i.e. 60°C) for pH 7 and pH 9.
After preparation, each test solution was placed in a thermostatically controlled waterbath at the specified temperature, and in the dark. For pH 7 at 60°C, the concentration of the test substance was determined immediately after preparation (t=0) and 23, 24, and 26 hours after t=0. For pH 9 at 60°C, the concentration of the test substance was determined immediately after preparation (t=0) and 16, 17 and 19 hours after t=0. At each sampling point, a 2 ml sample was taken for pretreatment and analysis. The logarithms of all relative concentrations were plotted against time for these pH values.
For each test solution, the pH value of each sample was measured at room temperature.

Buffers:

0.05 M acetate buffer pH 4: sodium acetate/acetic acid/Milli-Q water
0.05 M phosphate buffer pH 7: potassium dihydrogen phosphate/ sodium hydroxide/Milli-Q water
0.05 M borate buffer pH 9: boric acid/potassium chloride/sodium hydroxide/Milli-Q water

Duration of test

Duration of test 1

Duration:

2.4 h

pH:

4

Temp.:

50 °C

Initial conc. measured:

250 mg/L

Duration of test 2

Duration:

5 d

pH:

7

Temp.:

50 °C

Initial conc. measured:

1 659 mg/L

Duration of test 3

Duration:

19 h

pH:

7

Temp.:

60 °C

Initial conc. measured:

1 406 mg/L

Duration of test 4

Duration:

7 h

pH:

7

Temp.:

70 °C

Initial conc. measured:

1 648 mg/L

Duration of test 5

Duration:

5 d

pH:

9

Temp.:

50 °C

Initial conc. measured:

1 576 mg/L

Duration of test 6

Duration:

26 h

pH:

9

Temp.:

60 °C

Initial conc. measured:

1 722 mg/L

Duration of test 7

Duration:

8 h

pH:

9

Temp.:

70 °C

Initial conc. measured:

1 649 mg/L

Number of replicates:

Two replicate analyses

Positive controls:

no

Negative controls:

no

Results and discussion

Preliminary study:

At pH 4, a decrease in concentration > 50% was observed after 2.4 hours (half-life time at 25°C < 1 day). At pH 7 and pH 9, a decrease in concentration < 50% after 2.4 hours but > 10% after 5 days was observed.

Test performance:

No further testing was necessary at pH 4. Subsequent tests were performed at pH 7 and pH 9.

Transformation products:

not specified

Total recovery of test substance (in %)

% Recovery:

10

pH:

4

Temp.:

50 °C

Duration:

2.4 h

Dissipation DT50 of parent compound

Dissipation DT50 of parent compound 1

pH:

7

Temp.:

60 °C

Hydrolysis rate constant:

0.029 h-1

DT50:

23.7 h

Type:

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

Remarks on result:

other: y = -0.0127x + 2.000

Dissipation DT50 of parent compound 2

pH:

7

Temp.:

70 °C

Hydrolysis rate constant:

0.088 h-1

DT50:

7.84 h

Type:

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

Remarks on result:

other: y = -0.0384x + 1.996

Dissipation DT50 of parent compound 3

pH:

9

Temp.:

60 °C

Hydrolysis rate constant:

0.021 h-1

DT50:

0.053 h

Type:

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

Remarks on result:

other: y = -0.0089x + 2.000

Dissipation DT50 of parent compound 4

pH:

9

Temp.:

70 °C

Hydrolysis rate constant:

0.053 h-1

DT50:

13.1 h

Type:

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

Remarks on result:

other: y = -0.0230x + 2.000

Details on results:

See table below.

Any other information on results incl. tables

Code pH -temp.	Measured pH value	Time [hours]	Concentration test substance^1 [mg/l]	Relative concentration [%]	Logarithm relative conc.
7-60°C	7.0	0	1406	100	2.00
	7.0	16	883	63	1.80
	7.0	17	854	61	1.78
	7.0	19	806	57	1.76
9-60°C	9.0	0	1722	100	2.00
	9.0	23	1071	62	1.79
	9.0	24	1055	61	1.79
	9.0	26	1009	59	1.77
7-70°C	7.1	0	1648	100	2.00
	7.1	3	1244	75	1.88
	7.0	4	1132	69	1.84
	7.0	4.5	1087	66	1.82
	7.0	6	966	59	1.77
	7.0	7	889	54	1.73
9-70°C	9.0	0	1649	100	2.00
	9.0	4	1358	82	1.92
	9.0	4.5	1299	79	1.90
	9.0	5	1262	77	1.88
	9.0	6	1183	72	1.86
	9.0	7	1133	69	1.84
	9.0	8	1084	66	1.82

 ¹      Mean of duplicate analysis. The maximum deviation between the responses was < 10%.

Applicant's summary and conclusion

Validity criteria fulfilled:

yes

Conclusions:

STI571 Y5A is hydrolytically unstable (half-life time at 25°C < 1 day) in aqueous solutions buffered at pH 4.
At pH 7, the half-life times are 23.7 hours (60°C) and 7.84 hours (70°C). From these values the half-life time at 25°C in aqueous solutions buffered at pH 7 was calculated to be 2040 hours.
At pH 9, the half-life times are 33.7 hours (60°C) and 13.1 hours (70°C). From these values the half-life time at 25°C in aqueous solutions buffered at pH 9 was calculated to be 1523 hours.