(E)-4-Ethoxy-1,1,1-trifluoro-3-buten-2-one (stabilized with BHT)

Dissociation constant

Administrative data

Endpoint:

dissociation constant

Data waiving:

study technically not feasible

Justification for data waiving:

the study does not need to be conducted because the substance is hydrolytically unstable (half-life less than 12 hours)

the study does not need to be conducted because the substance has no ionic structure

Cross-reference

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

key study

Study period:

23-24 Aug. 2006

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

The study was conducted according to an internationally recognised method, and under GLP. The substance is adequately characterised with its purity. A Klimisch score of 2 was however assigned due to several deviations from OECD 111 guideline. Only a preliminary test (Tier 1) was performed at pH = 4, 7 and 9. Instead of being performed at 50 +/- 0.5 °C, it was performed at 7 +/- 1 °C. This temperature was selected since ETFBO is not stable in water at 20 °C. This deviation to the guideline was tolerated; especially considering that the use of this low temperature was a worst-case scenario that allowed to demonstrate that the registered substance hydrolyses quickly even at low temperatures. No Tier 2 and Tier 3 were conducted despite the fact the substance was unstable and the transformation products were not identified. Nevertheless, this study brought evidences of the quick hydrolyses of the registered subtance and was therefore considered as reliable with restriction for use into the registration dossier. This quick hydrolysis was supported by the water solubility study (Spruit & Mak, 2005; see IUCLID section 4.8) which demonstrated that, at 20 °C, in the solutions of the three solubility tests, the target peak at the retention time of 5.2 min was not detectable, while a peak at 8.4 min, which is not in the chromatogram of the standard solutions of ETFBO, was observed. At the end, the use of this substance as an intermediate under strictly controlled conditions mitigates the need to go deeper in the analysis of transformation products.

Reason / purpose for cross-reference:

other: Supporting information

Qualifier:

according to guideline

Guideline:

OECD Guideline 111 (Hydrolysis as a Function of pH)

Version / remarks:

2004

Deviations:

yes

Remarks:

See in the field "Principles of method if other than guideline".

Principles of method if other than guideline:

The report mentions that the study was conducted according to OECD 111 guideline. Only a preliminary test (Tier 1) was performed at pH = 4, 7 and 9. Instead of being performed at 50 +/- 0.5 °C, it was performed at 7 +/- 1 °C. This temperature was selected since ETFBO is not stable in water at 20 °C. This deviation to the guideline was tolerated; especially considering that the use of this low temperature was a worst-case scenario that allowed to demonstrate that the registered substance hydrolyses quickly even at low temperatures. No Tier 2 and Tier 3 were conducted despite the fact the substance was unstable and the transformation products were not identified.

GLP compliance:

yes

Radiolabelling:

no

Analytical monitoring:

yes

Details on sampling:

- Sampling intervals for the parent product:
* 0, 25 and 48 min at pH = 4
* 0, 19 and 40 min at pH = 7
* 0, 20 and 41 min at pH = 9
- Sampling method: At the start of the study, 0.1 mL ETFBO test solution was pipetted into a Gas Chromatography (GC) vial already containing 0.9 mL acetonitrile, capped and mixed. Immediately hereafter the solution was injected on the GC system. Directly after each GC run, the next sample was prepared (by diluting 0.1 mL ETFBO test solution with 0.9 mL acetonitrile) and the exact time of sampling was recorded. For all solutions (pH = 4, 7 and 9), three samples were prepared since no measurable amounts of ETFBO were found in all solutions after the third injection.
- Sample storage conditions before analysis: No storage, GC analysis immediately after sampling.
No further data.

Buffers:

- Buffer at pH = 4: A 2 M acetic acid solution was prepared by diluting ca. 12 mL acetic acid in 100 mL purifed water. Then a 0.05 M sodium acetate solution was prepared by weighing 4.109 g sodium acetate and dissolving them in ca. 800 mL purified water. The pH of this last solution was adjusted with the 2 M acetic acid solution to pH = 4.02. The solution was made up to 1 L with purified water to obtain a 0.05 M acetate buffer solution with pH = 4.0.
- Buffer at pH = 7: 6.784 g KH2PO4 were weighed and dissolved in ca. 800 mL purified water. The pH was adjusted with 0.5 M sodium hydroxide solution to pH = 7.00. The solution was made up to 1 L with purified water to obtain a 0.05 M phosphate buffer solution with pH = 7.0.
- Buffer at pH = 9: 19.007 g Na2B4O7.10H2O were weighed and dissolved in ca. 800 mL purified water. The pH was adjusted with 0.5 M HCl solution to pH = 9.01. The solution was made up to 1 L with purified water to obtain a 0.05 M borate buffer solution with pH = 9.0.

Details on test conditions:

TEST SYSTEM
- Test flasks: Three separate volumetric flasks (one per pH condition).
- Lighting: In the dark.
- Stirring: At the beginning of the experiment, vigorous shaking was applied until all ETFBO was dissolved. Afterwards a stir bar was added so the solutions could be mixed constantly.
- Incubation: For at least 2 hours at 7 +/- 1 °C. This temperature was selected since ETFBO is not stable in water at 20 °C.
No further data.

TEST MEDIUM
- Volume used per treatment: 100 mL.
- Kind and purity of water: The purified water used to prepare buffered solutions (see in the field "Buffers") was prepared by Solvay Pharmaceuticals according to the methods of the European Pharmacopoeia and the USP Purified water.
- Preparation of test medium: According to OECD 111 guideline, the concentration of the test substance should not exceed 0.01 M. Therefore, ETFBO solutions with concentrations of 1813, 1808 and 1774 mg/L were prepared in the buffered solutions at pH = 4, 7 and 9, respectively.
- Renewal of test solution: No renewal because the study was stopped after the third sampling time performed after 40 to 50 min depending on the pH condition.
No further data.

OTHER TEST CONDITIONS
No further data.

Duration:

48 min

pH:

4

Temp.:

7 °C

Initial conc. measured:

1 813 mg/L

Remarks:

Nominal (and not measured) concentration

Duration:

40 min

pH:

7

Temp.:

7 °C

Initial conc. measured:

1 808 mg/L

Remarks:

Nominal (and not measured) concentration

Duration:

41 min

pH:

9

Temp.:

7 °C

Initial conc. measured:

1 774 mg/L

Remarks:

Nominal (and not measured) concentration

Number of replicates:

For each pH condition, one sample was collected at each sampling time.

Positive controls:

no

Negative controls:

no

Statistical methods:

No statistics seem to have been performed (no information in the report).

Transformation products:

not measured

% Recovery:

< 1

pH:

4

Temp.:

7 °C

Duration:

48 min

% Recovery:

< 1

pH:

7

Temp.:

7 °C

Duration:

40 min

% Recovery:

< 1

pH:

9

Temp.:

7 °C

Duration:

41 min

Key result

pH:

4

Temp.:

7 °C

DT50:

< 30 min

Key result

pH:

7

Temp.:

7 °C

DT50:

< 30 min

Key result

pH:

9

Temp.:

7 °C

DT50:

< 30 min

Details on results:

As it can be seen in the table reported in the field "Any other information on results incl. tables", the rate of hydrolysis at the start of the study (sampling time = 0 min) was higher at higher pH (72.6 % hydrolysis at pH = 9, 45.2 % at pH = 7 and 33.4 % at pH = 4). At the second sampling time (after 19 to 25 min depending on the pH condition), no measurable to negligible amounts of ETFBO were found whatever the pH condition. At the third sampling time (after 40 to 48 min depending on the pH condition), no measurable amounts of ETFBO were found indicating that all ETFBO was hydrolysed whatever the pH condition.

Since the half-life time at 7 °C was shorter than 30 minutes at pH = 4, 7 and 9, the half-life time of ETFBO at 20 °C for pH = 4, 7 and 9 was also reported as shorter than 30 min and no additional testing was performed.

Summarised results of the hydrolysis of ETFBO at pH = 4, 7 and 9: 

Buffer solution	Nominal concentration (mg/L)*	Sampling time (min)	Measured concentration (mg/L)*	Hydrolysis (%)
pH = 4	181.3	0	120.7	33.4
		25	1.0**	> 99
		48	< 1**	> 99
pH = 7	180.8	0	99.0	45.2
		19	1.4**	> 99
		40	< 1**	> 99
pH = 9	177.4	0	48.6	72.6
		20	< 1**	> 99
		41	< 1**	> 99

* The concentrations reported were those of the 10 times diluted samples.

** Only an indication of content could be calculated since calibrated range was between 18.12 and 1812 mg/L.

Validity criteria fulfilled:

yes

Remarks:

See in the field "Overall remarks".

Conclusions:

The half-life time of ETFBO at 7 °C was demonstrated to be shorter than 30 minutes at pH = 4, 7 and 9, and therefore the half-life time at 20 °C for pH = 4, 7 and 9 was also reported as shorter than 30 min.

Executive summary:

Hydrolysis of ETFBO was investigated in a GLP-compliant study performed according to OECD test guideline 111.

ETFBO solutions with concentrations of 1813, 1808 and 1774 mg/L were prepared in buffered solutions at pH = 4, 7 and 9, respectively. Three separate volumetric flasks (one per pH condition) containing 100 mL test solutions were incubated in the dark at 7 +/- 1 °C. This temperature was selected since ETFBO is not stable in water at 20 °C. Samples were collected in each volumetric flask at three sampling times:

- after 0, 25 and 48 min at pH = 4

- after 0, 19 and 40 min at pH = 7

- after 0, 20 and 41 min at pH = 9

ETFBO concentrations were then measured using gas chromatography.

The hydrolysis process began from the start of the study (sampling time = 0 min) with a rate which was higher at higher pH (72.6 % hydrolysis at pH = 9, 45.2 % at pH = 7 and 33.4 % at pH = 4). At the second sampling time (after 19 to 25 min), no measurable to negligible amounts of ETFBO were found whatever the pH condition. At the third sampling time (after 40 to 48 min), no measurable amounts of ETFBO were found indicating that all ETFBO was hydrolysed whatever the pH condition.

The half-life time of ETFBO at 7 °C was thus demonstrated to be shorter than 30 minutes at pH = 4, 7 and 9, and therefore the half-life time at 20 °C for pH = 4, 7 and 9 was also reported as shorter than 30 min. Transformation products were not investigated during this study.