Reaction mass of sulfonium, dodecylethyl[1-(2-methoxy-2-oxoethyl)-3-oxo-3-(pentyloxy)propyl]-, tetrafluoroborate(1-)(1:1) and sulfonium, dodecylethyl[3-methoxy-1-(2-methoxy-2-oxoethyl)-3-oxopropyl]-, tetrafluoroborate(1-)(1:1) and sulfonium, dodecylethyl[3-oxo-1-[2-oxo-2-(pentyloxy)ethyl]-3-(pentyloxy)propyl]-, tetrafluoroborate(1-)(1:1)

Hydrolysis

Administrative data

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

key study

Study period:

September 14, 2017

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

2017

Report date:

2017

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 111 (Hydrolysis as a Function of pH)

GLP compliance:

no

Remarks:

The study was conducted in a NMR laboratory not under GLP nor ISO compliant. This laboratory was chosen because NMR could quantify both parent and degradation products without the need of certified analytical standards, which were not available.

Test material

Test material information

Constituent 1

Reference substance name:

(1,5-dimethoxy-1,5-dioxopentan-3-yl)(dodecyl)ethylsulfanium; [1,5-dioxo-1,5-bis(pentyloxy)pentan-3-yl](dodecyl)ethylsulfanium; dodecyl(ethyl)[1-methoxy-1,5-dioxo-5-(pentyloxy)pentan-3-yl]sulfanium; tris(tetrafluoroboranuide)

EC Number:

943-993-4

Cas Number:

2220260-54-6

Molecular formula:

not applicable for multi-constituent.

IUPAC Name:

(1,5-dimethoxy-1,5-dioxopentan-3-yl)(dodecyl)ethylsulfanium; [1,5-dioxo-1,5-bis(pentyloxy)pentan-3-yl](dodecyl)ethylsulfanium; dodecyl(ethyl)[1-methoxy-1,5-dioxo-5-(pentyloxy)pentan-3-yl]sulfanium; tris(tetrafluoroboranuide)

Test material form:

liquid

Details on test material:

Multi-constituent substance.
degree of purity: >=94%

Radiolabelling:

no

Study design

Analytical monitoring:

yes

Details on sampling:

- Sampling intervals for the parent products: Hydrolysis of the MTDID 47403 was evaluated at pH 4, 7 and 9 and at three temperature (10 °C, 25°C, and 50 °C). For each pH and temperature combination, MTDID 47403 concentrations in aqueous buffer systems were measured in sufficient timepoints to obtain accurate half-lives. The concentration of the MTDID 47403 was determined from the integral of either the methyl ester or sulfonium ion beta-CH2 resonance relative to the water resonance (used as normalization) using NMR techniques.
- Sampling method: Solutions of 0.5 mg/mL MTDID 47403 were made by dissolving the test substance in an appropriate amount of D2O buffer solution and vigorously mixing for ~15-30 seconds before transfer to a 5mM NMR tube. For the 10 °C experiments, the buffer was equilibrated at 4 °C in a refrigerator prior to mixing. For the 25 °C and 50 °C experiments, the buffer was equilibrated a room temperature (~20C). The amount of hydrolysis in the “dead” time between mixing and the first NMR experiment was not measured, so starting with a temperature below the final set point ensures the least amount of hydrolysis. The 5mM NMR tube was quickly transferred to a Bruker 600 MHz NMR spectrometer equilibrated at the desired temperature for the study. A temperature equilibration time of 0.5-2 minutes was used depending upon the difference in temperature between the sample and the NMR temperature. Automatic locking, tuning, and shimming procedures were performed by the NMR spectrometer software, resulting in a total dead time between mixing acquisition of the first NMR experiment of approximately 5 minutes.
- Sampling methods for the volatile compounds, if any: None
- Sampling intervals/times for pH measurements: None
- Sampling intervals/times for sterility check: None
- Sample storage conditions before analysis: None
- Other observation, if any (e.g.: precipitation, color change etc.):

Buffers:

- pH: 4, 7, 9
- Type and final molarity of buffer:
pH 4 :100 mM Oxolic acid + 100 mM sodium oxalate adjusted to pH 4 with NaOH; Oxalate was used instead of a phthalate buffer because of the lack of protons that would interfere with the NMR analysis.
pH 7: 200 mM sodium phosphate adjusted to pH 7 with NaOH;
pH 9: 200 boric acid adjusted to pH 9 with NaOH;

The buffers were diluted with D2O to produce 2 mM buffer solutions that were directly used for the NMR hydrolysis experiments (50 µL 200 mM stock with 4.95 mL D2O).

Results and discussion

Preliminary study:

An accelerated hydrolysis evaluations were conducted by mixing ~ 100 -130 mg MTDID 47403 samples with 1.6 -1.7 mL pH 4 and pH 10 buffer solutions. The mixtures were subsequently mixed at room temperature (22-23 °C) on a horizontal shaker and heated at 70-80 °C on a steam table for periods of about 4 days. The hydrolysis reactions at both pH conditions yielded aqueous phases and water insoluble oil phases. Aliquots of the aqueous phases were removed first and diluted with deuterated acetonitrile (CD3CN) for NMR analysis. Once the aliquots of the aqueous phases were removed, the oil phases were isolated from the hydrolysis reaction mixtures by extraction with 0.7-1.0 mL aliquots of deuterated chloroform (CDCl3). Initial 1D 600.1 MHz 1H-NMR and qualitative 150.8 MHz 13CNMR spectra were acquired. The CDCl3 extract solutions were also used for the acquisition of various 2D NMR experiments to facilitate assignment of the signals observed in the 1D spectra. The 2D spectra included 1) 1H/13C-NMR gradient heteronuclear single quantum coherence (gHSQC) experiments to permit the observation of 1-bond 1H/13C spin-spin coupling correlations, 2) 1H/13C-NMR gradient heteronuclear multiple bond correlation (gHMBC) experiments to permit the observation of 2-3 bond 1H/13C spin-spin coupling correlations, and 3) 1H/1H gradient homonuclear correlated spectroscopy (1H-gCOSY) experiments to permit the observation of 1H/1H spin-spin coupling correlations. All of the NMR spectra were acquired using a Bruker Avance 600 FT-NMR spectrometer that was operating with a helium cooled 5 mm inverse-detection gradient cryoprobe at an analysis temperature of 25 ºC. Primary hydrolysis by-products of MTDID 47403 detected in the aqueous phases and oil phases are described in Fig 1.

Transformation products:

not measured

Dissipation DT50 of parent compound

Dissipation DT50 of parent compound 1

Key result

pH:

7

Temp.:

25 °C

Hydrolysis rate constant:

>= 0.051 - <= 0.085 min-1

DT50:

>= 8 - <= 14 min

Type:

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

Remarks on result:

other: Half life of 8 minutes based on the sulfonium ion beta-CH2 resonances intensity; Half life of 14 minutes based on the methyl ester resonances intensity

Dissipation DT50 of parent compound 2

Key result

pH:

4

Temp.:

25 °C

Hydrolysis rate constant:

>= 0.005 - <= 0.006 min-1

DT50:

>= 112 - <= 151 min

Type:

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

Remarks on result:

other: Half life of 112 minutes based on the sulfonium ion beta-CH2 resonances intensity; Half life of 151 minutes based on the methyl ester resonances intensity

Dissipation DT50 of parent compound 3

Key result

pH:

9

Temp.:

25 °C

Hydrolysis rate constant:

0.165 min-1

DT50:

4 min

Type:

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

Remarks on result:

other: Based on the methyl ester resonances intensity

Other kinetic parameters:

Hydrolysis is considered a first order reaction:

ln(Ct/C0) = -kt;

The half-life (t1/2) of the first-order reaction calculated as follows:
t1/2 = [ln(2)/k]
Where:
k = hydrolysis first-order rate constant
t = time

The relative concentration of the MTDID 47403 was determined from the integral of either the methyl ester or sulfonium ion beta-CH2 resonance relative to the water resonance (used as normalization). A plot of the natural log of the relative molar concentration determined from the integrals vs time was plotted and fitted with linear regression to determine the first order rate constant for hydrolysis (k). Half-lives were calculated as 0.693/k.

Arrhenius plots can be generated as ln(k) vs 1/T (in Kelvin) for each pH condition.

Details on results:

Hydrolysis of MTDID 47403 is pH and temperature dependent. Fast hydrolysis rates were observed at higher pH and higher temperature (table 1, table 2).

At 25 °C, the measured hydrolysis half-lives for MTDID 47403 were 151, 14, and 4 minutes for pH 4, 7, and 9, respectively, based on the methyl ester resonance measurements; At the same temperature of 25 °C, the measured hydrolysis half-lives for MTDID 47403 were 112 and 8 minutes at pH 4 and 7, respectively, based on the sulfonium ion beta-CH2 resonance measurements. Half-life for sulfonium ion beta-CH2 resonance were not obtainable for the pH 9 conditions as hydrolysis kinetics were too fast.

Hydrolysis at pH 7 and 9 at 50 °C was faster than the dead time for the NMR experiment and no data was obtainable.

The methyl ester resonances have the best sensitivity due to the most number of protons per mole and the lack of J-coupling. However, this peak only reflects the di-methyl and methyl-pentyl MTDID 47403 species. The sulfonium ion beta-CH2 resonance is for all MTDID 47403 species; however, the signal to noise is much lower due to peak splitting from J-coupling and the low concentration of the analyte used. Therefore, there is more error in the line fitting for this resonance. As such, it is not entirely clear if the difference in calculated rate constants shown above reflect error or differences in reactivity between the methyl and pentyl MTDID 47403.

Any other information on results incl. tables

Table 1. Summary of MTDID 47403 Hydrolysis data for methyl ester resonance

pH	Temp (°C)	Hydrolysis rate (k) (min^-1)	Half-life (min)	1/T (Kevin)	ln(k)
4	10	0.0016	433	0.00353	-6.44
4	25	0.0046	151	0.00336	-5.38
4	50	0.042	17	0.00310	-3.17
7	10	0.024	29	0.00353	-3.73
7	25	0.051	14	0.00336	-2.98
9	10	0.061	11	0.00353	-2.80
9	25	0.165	4	0.00336	-1.80

 

Table 2 Summary of MTDID 47403 hydrolysis data for sulfonium ion beta-CH2 resonance

pH	Temp (°C)	Hydrolysis rate (k) (min^-1)	Half-life (min)	1/T (Kevin)	ln(k)
4	10	0.0022	315	0.00353	-6.12
4	25	0.0062	112	0.00336	-5.08
4	50	0.0558	12	0.00310	-2.89
7	10	0.0337	21	0.00353	-3.39
7	25	0.085	8	0.00336	-2.47

 

Applicant's summary and conclusion

Validity criteria fulfilled:

yes

Conclusions:

Hydrolysis of MTDID 47403 is pH and temperature dependent with fast hydrolysis rates observed at higher pH and higher temperature. At pH 7 and 25 °C, MTDID 47403 hydrolysis half-lives were 14 and 8 minutes, measured for methyl ester resonance and sulfonium ion beta-CH2 resonance, respectively.

Executive summary:

Hydrolysis of the MTDID 47403 was evaluated at pH 4, 7 and 9 and at three temperature (10 °C, 25°C, and 50 °C). For each pH and temperature combination, MTDID 47403 concentrations in aqueous buffer systems were determined from the integral of either the methyl ester or sulfonium ion beta-CH2 resonance relative to the water resonance (used as normalization) using Nuclear Magnetic Resonance Spectroscopy (NMR). Sufficient timepoints were measured to obtain an accurate half-lifes for each condition. The hydrolysis data showed first order rate constant behavior with good linear fits for a plot of the natural log of MTDID 47403 concentration as a function of time.

Hydrolysis of MTDID 40473 is pH and temperature dependent with fast hydrolysis rates observed at higher pH and higher temperature. At pH 7 and 25 °C, MTDID 40473 hydrolysis half lifes were 14 and 8 minutes, measured for methyl ester resonance and sulfonium ion beta-CH2 resonance, respectively.

This study is conducted similar to OECD111 test guideline. It is well documented with sufficient detail and suitable for PBT and risk assessment.