Registration Dossier

Administrative data

Endpoint:
hydrolysis
Type of information:
experimental study
Adequacy of study:
key study
Study period:
February 17, 2017 - March 27, 2017
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report Date:
2017

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 111 (Hydrolysis as a Function of pH)
GLP compliance:
no
Remarks:
Developmental work on the hydrolytic degradation was initiated in the 3M Environmental Lab (OECD 111 is on the Lab ISO 17025 scope of accreditation). It was decided that ecotox testing would be performed on the degradants instead of the parent.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Specific details on test material used for the study:
Source and lot/batch No.of test material: 629582
-Purity: 98.3%
- Expiration date of the lot/batch:June 9, 2017
Radiolabelling:
no

Study design

Analytical monitoring:
yes
Details on sampling:
- Sampling intervals for the parent compound: Hydrolysis of the MTDID 15670 cation was evaluated at pH 4, 7 and 9. Six samples, including the cation samples in triplicate, method blank, method spike and matrix spike, were prepared at three temperature (4 °C, 23°C, and 50 °C). The cation hydrolysis was conducted in the pH buffers at 4°C because of its rapid hydrolysis at pH 7 and pH 9 at 23°C and 50 °C. At least 6 time points were prepared for each cation hydrolysis experiment. For each pH and temperature combination, MTDID 15670 concentrations in aqueous buffer systems were measured at a minimum of six discrete time points after initial dosing of the test system. The LC/MS/MS signal for the anion was significantly depressed in all three pH buffers (< 35%) after sample preparation at ambient temperature; the low recoveries of anion in all pH buffers prohibited a reliable hydrolysis evaluation of the anion, therefore it was not evaluated further in this study.
- Sampling method: Test system vials were 20-mL amber-glass volatile organics analysis (VOA) vials. Ten mL of each pH buffer was added to each vial at ambient temperature (23 ± 1°C), except for the experiment at 4°C, which was prepared on the ice using the cold buffer solutions (4°C). Then, 0.1 mL of nominal 10 mg/mL MTDID 15670 (cation + anion in DMSO) was spiked in the cation samples and the matrix spike sample; and 0.1 mL of DMSO was spiked in the method blank and method spike samples for all the tested pH and temperature conditions. The samples were vortexed and wrapped with aluminum foil and then were placed in the refrigerator (4°C) or the incubator shaker (50°C) at 100 RPM. The samples were removed at each time point for the determination of the cation concentrations. Then, 0.1 mL of nominal 10 mg/mL MTDID 15670 was spiked in the method spike sample and the matrix spike sample, which were vortexed and diluted using the same procedure as other samples for determination by LC/MS/MS.
- Sampling methods for the volatile compounds, if any: None
- Sampling intervals/times for pH measurements: Additional two samples prepared as the pH buffer trackers with/without MTDID 15670. The pH tracker without MTDID 15670 was measured using pH meter and the pH tracker with MTDID 15670 was measured using pH paper strip (PEHANON pH Indicator Strips pH 6.0-8.1).
- Sampling intervals/times for sterility check: None
- Sample storage conditions before analysis: 4 °C
- Other observation, if any (e.g.: precipitation, color change etc.): The cation in water was strongly adsorbed on the surface of glass vessels. The adsorption of the cation on the glass surface was dramatically reduced using 5% aqueous acetic acid-treated I-Chem vials and autovials. Acid-treated I-Chem vials and autovials were used for MTDID 15670 stock and working solutions, calibration standards and sample autovials for LC/MS/MS.
Buffers:
- pH: 4, 7, 9
- Type and final molarity of buffer:
pH 4: 0.1 M potassium biphthalate + 0.1 N NaOH;;
pH 7: 0.1 M monopotassium phosphate + 0.1 N NaOH;
pH 9: 0.1 M H3BO3 in 0.1 M KCl + 0.1 N NaOH

The buffers were sparged with nitrogen for 20 min to remove the oxygen before the autoclave. There was about 0.01 pH unit increase after the autoclave. The autoclaved buffers were placed in the refrigerator (4°C) for storage prior to use.

Results and discussion

Preliminary study:
Initial accelerated hydrolysis evaluations were conducted at pH 4 and pH 10 (70-80°C; 6-24 hours) and monitored by 1D and 2D 13C- and 1H-NMR spectroscopy. At pH 10 it was found that an oil-like water insoluble substance formed, which was separated from the water phase and identified as primarily dodecyl ethyl sulfide with low levels of crotononitrile (mixture of cis and trans isomers). The water phase contained primarily crotononitrile (mixture of cis and trans). At pH 4 (single experiment) crotonitrile and unreacted MTDID 15670 were identified in the water phase; oil phase was not analyzed at pH 4.

In the method suitability test, the effect of the vessel types on MTDID 15670 was tested in the buffers of pHs 4, 7 and 9 at ambient temperature (23 °C). The cation concentrations were <0.515% to <1.08% (LLOQ × dilution factor) at pH 9 in all the vial types due to apparent rapid hydrolysis at pH 9 at ambient temperature. The cation recoveries at pH 7 were all less than 50% (38.2%-45.8%) also due to apparent hydrolysis at that pH at ambient temperature (23°C). Based on this, it was concluded that the hydrolysis rate could not be measured accurately at pH 7 & pH 9 at 23 °C due to fast hydrolysis, and no further testing was performed.
Transformation products:
yes
Identity of transformation productsopen allclose all
No.:
#1
Reference
Reference substance name:
Unnamed
Inventory number:
InventoryMultipleMappingImpl [inventoryEntryValue=EC 225-335-1]
IUPAC name:
but-2-enenitrile
Identity:
2-Butenenitrile
CAS number:
4786-20-3
Molecular formula:
C4H5N
Molecular weight:
67.089
SMILES notation:
C\C=C\C#N
InChl:
InChI=1/C4H5N/c1-2-3-4-5/h2-3H,1H3
No.:
#2
Reference
Reference substance name:
Unnamed
IUPAC name:
1-(ethylsulfanyl)dodecane
Molecular formula:
C14H30S
Molecular weight:
230.453
SMILES notation:
CCSCCCCCCCCCCCC
Dissipation half-life of parent compoundopen allclose all
Key result
pH:
7
Temp.:
4 °C
Hydrolysis rate constant:
0.333 h-1
Half-life:
2.08 h
Type:
(pseudo-)first order (= DT50)
Remarks on result:
other: For the Cation only
pH:
4
Temp.:
50 °C
Hydrolysis rate constant:
0.151 h-1
Half-life:
4.59 h
Type:
(pseudo-)first order (= DT50)
Remarks on result:
other: For the Cation only
pH:
9
Temp.:
4 °C
Half-life:
< 20 min
Remarks on result:
other: The concentrations of the cation were <15.5 ng/mL (LLOQ × dilution factor) at the time point of 20 min
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
C0 and Ct are the concentrations of the cation at times 0 and t.
Details on results:
The cation was hydrolyzed more than 95% within 10 h at pH 7 and 4°C (Table 1). The half-life of the cation was 2.08 h at pH 7 and 4±1 °C based on the first order reaction of the cation at pH 7 (y=0.3334x and R^2=0.9874) (Fig. 1). In addition, the relative standard deviations (RSD) of the cation concentrations were >25% at 6h, 8h and 10 h time points because most of the cation has been hydrolyzed and the lower concentrations led to the bigger deviations.

The cation was relatively stable at pH 4 and 4°C during a period of approximately 10 h (Table 2) (Fig. 1). The worst-case half-life was 44.4 h based on the cation concentration. Therefore, its hydrolysis at pH 4 was further performed at 50°C. The cation hydrolyzed more than 95% after 24 hours at pH 4 and 50°C (Table 3). The half-life of the cation was 4.59 h at pH 4 and 50 °C (y=0.151x and R^2=0.9871) (Fig. 1).

The concentrations of the cation at pH 9 were <15.5 ng/mL (LLOQ × dilution factor) at the time point of 20 min at 4 °C. Therefore, the half-life of the cation at pH 9 at 4 °C was too short to be calculated. In addition, the cation recoveries in method spike and matrix spike at pH 9 and 4 °C were very low ( < 10%) due to the rapid hydrolysis.

The LC/MS/MS signal of the anion was suppressed in all three pH buffers evaluated, with recoveries < 35%, and therefore anion stability was not studied further.

Any other information on results incl. tables

Table 1. MTDID 15670 Cation Hydrolysis in pH 7 buffer and 4°C

Time Point

Spiked conc. (µg/mL)

Average measured conc. (μg/mL) *

RSD (%)

% of the cation  remaining

1 (20 min)

69.8

57.0

1.8

81.7

2 (2 h)

69.8

28.9

6.9

41.3

3 (4 h)

69.8

16.3

8.4

23.4

4 (6 h)

69.8

8.26

38

11.8

5 (8 h)

69.8

5.63

33

8.06

6 (10 h)

69.8

2.63

27

3.77

 *Average of triplicate samples

Table 2. MTDID 15670 Cation Hydrolysis in pH 4 Buffer and 4 °C

Time Point

Spiked conc. (µg/mL)

Average measured conc. (μg/mL)*

RSD (%)

% of cation remaining

1 (20 min)

69.8

65.3

1.6

93.5

2 (2 h)

69.8

71.2

4.0

102

3 (4 h)

69.8

66.6

5.8

95.3

4 (6 h)

69.8

60.8

11

87.1

5 (8 h)

69.8

58.2

14

83.3

6 (10 h)

69.8

63.7

1.3

91.2

 *Average of triplicate samples

 Table 3. MTDID 15670 Cation Hydrolysis in pH 4 Buffer and 50 °C

Time Point

Spiked conc. (µg/mL)

Average measured conc. (μg/mL)*

RSD (%)

% of cation remaining

1 (20 min)

69.8

67.7

0.76

97.3

2 (2 h)

69.8

70.3

1.8

101

3 (4 h)

69.8

58.5

3.2

84.2

4 (6 h)

69.8

44.5

8.4

64.1

5 (8 h)

69.8

37.7

2.2

54.2

6 (10 h)

69.8

26.3

3.2

37.9

7 (12 h)

69.8

20.6

1.8

29.6

8 (24 h)

69.8

2.47

9.1

3.57

  *Average of triplicate samples

Applicant's summary and conclusion

Validity criteria fulfilled:
yes
Conclusions:
MTDID15670 cation is hydrolytically unstable with measured hydrolysis half-life values of 2.08 hours at pH 7 and 4 °C, 4.59 hours at pH 4 and 50 °C. The half-life of the cation at pH 9 was too short be determined analytically. The hydrolytic rate constant and resultant half-life are dependent on pH and temperature.
Executive summary:

Hydrolysis of MTDID 15670 was investigated according to OECD 111 guideline “Hydrolysis as a Function of pH”.

MTDID 15670 MTDID 15670 is composed of an organic sulfonium (cation) component and an inorganic tetrafluoroborate (anion) component. Both were evaluated for hydrolytic stability during this study. Triplicate samples were prepared at three pHs (4, 7, and 9) and at three different temperatures (4°C, 23°C, and 50°C). For each pH and temperature combination, a minimum of six discrete time points (from 20 minutes to 10 hours) after initial dosing of the test system were prepared. MTDID 15670 cation and anion concentrations in aqueous buffer systems were measured separately using LC/MS/MS. The hydrolysis rate and the half-life values (t1/2) were calculated based on assumption of first order kinetics.  

LC/MS/MS signal for the anion was significantly depressed in all three pH buffers (< 35%) after sample preparation at ambient temperature; the low recoveries of anion in all pH buffers prohibited a reliable hydrolysis evaluation of the anion, therefore it was not evaluated further in this study.

MTDID15670 cation is hydrolytically unstable, the hydrolytic rate constant and resultant half-life are dependent on pH and temperature. The half-life of the cation at pH 7 was 2.08 hours at 4 °C, but was too fast to be accurately determined at 23°C and was not evaluated at 50°C. The half-life of the cation at pH 4 was 44.4 hours at 4°C, and 4.59 h at 50°C, but was not evaluated at 23°C. The hydrolysis of cation at pH 9 was too rapid at 4°C and 23°C to obtain any accurate kinetic measurements, and was not performed at 50 °C. The hydrolysis products of the cation were identified in another study by NMR to be crotononitrile (cis and trans isomers) and dodecyl ethyl sulfide by 1D and 2D 1H- and 13C-NMR evaluations.

The hydrolysis study is conducted according to OECD guideline but not in compliance with GLP. This study is considered reliable with restriction and a key study.