Methyl 3-mercaptopropionate

Hydrolysis

Administrative data

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

key study

Study period:

to 2003-06-02

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study conducted according to OECD Guideline 111 "Hydrolysis as a Function of pH"

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2003

Report date:

2003

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 111 (Hydrolysis as a Function of pH)

Deviations:

yes

Remarks:

solutions not analyzed on day 5 in preliminary test.

Principles of method if other than guideline:

N/A

GLP compliance:

yes

Remarks:

Stated, no certificate provided.

Test material

Test material information

Constituent 1

Reference substance name:

Methyl 3-mercaptopropionate

EC Number:

220-912-4

EC Name:

Methyl 3-mercaptopropionate

Cas Number:

2935-90-2

Molecular formula:

C4H8O2S

IUPAC Name:

methyl 3-sulfanylpropanoate

Details on test material:

- Name of test material (as cited in study report): methyl 3-mercaptopropionate
- Molecular formula (if other than submission substance): N/A
- Molecular weight (if other than submission substance): N/A
- Smiles notation (if other than submission substance): N/A
- InChl (if other than submission substance): N/A
- Structural formula attached as image file (if other than submission substance): N/A
- Substance type: active
- Physical state: colorless liquid

Specific details on test material used for the study:

Details on properties of test surrogate or analogue material (migrated information):
N/A

Radiolabelling:

no

Study design

Analytical monitoring:

yes

Details on sampling:

- Sampling intervals for the parent/transformation products: see below
- Sampling method: N/A
- Sampling methods for the volatile compounds, if any: N/A
- Sampling intervals/times for pH measurements: see below
Sampling times and temperature of the oven
:Preliminary test
pH 4.0, 7.0 and 9.0
Amount of test item used for preparation of buffer solution:
⋅ 0.1045 g for pH 4.0,
⋅ 0.0994 g for pH 7.0,
⋅ 0.1042 g for pH 9.0.
Volume of volumetric flask for each buffer solution: 100 mL
Sampling times and temperature of the oven:
⋅ 0 hour, 2.4 hours and 72 hours at 50 deg. C.

First temperature (27 deg. C)
pH 4.0, 7.0 and 9.0
Amount of test item used for preparation of buffer solution:
⋅ 0.5496 g for pH 4.0,
⋅ 0.5420 g for pH 7.0,
⋅ 0.5432 g for pH 9.0.
Volume of volumetric flask for each buffer solution: 500 mL
Sampling times and temperature of the oven:
⋅ 0, 338.5, 535.0, 653.5, 749.5, 869.5 and 918.0 hours (pH 4.0),
⋅ 0, 144.0, 168.0, 171, 175.0, 192.0, 319.5 and 388.5 hours (pH 7.0),
⋅ 0, 23, 24, 25, 30, 31 and 32 hours (pH 9.0).

Second temperature (37 deg. C)
pH 4.0, 7.0 and 9.0
Amount of test item used for preparation of buffer solution:
⋅ 0.5496 g for pH 4.0,
⋅ 0.5420 g for pH 7.0,
⋅ 0.5432 g for pH 9.0.
Volume of volumetric flask for each buffer solution: 500 mL
Sampling times and temperature of the oven:
⋅ 0, 316.5, 388.3, 535.0, 653.5, 749.5 and 869.5 hours (pH 4.0),
⋅ 0, 74.0, 144.0, 168.0, 171.0, 175.0, 192.0, 319.5 and 388.3 hours (pH 7.0),
⋅ 0, 5.0, 6.3, 6.8, 7.3, 7.5 and 8.5 hours (pH 9.0).

Repeated temperature (37 deg. C)
pH 4.0, 7.0 and 9.0
Amount of test item used for preparation of buffer solution:
⋅ 0.2179 g for pH 4.0,
⋅ 0.2175 g for pH 7.0,
⋅ 0.2145 g for pH 9.0.
Volume of volumetric flask for each buffer solution: 200 mL
Sampling times and temperature of the oven:
⋅ 0, 334.0, 381.5, 474.0, 522.5, 642.5 and 715 hours (pH 4.0),
⋅ 0, 190.0, 214.5, 238.0, 280.0, 354 and 381.5 hours (pH 7.0),
⋅ 0, 6.25, 6.75, 7.25, 7.75, 8.50 and 9.00 hours (pH 9.0).

Temperature for pH 1.2 (37 deg. C)
Amount of test item used for preparation of buffer solution: 0.2233 g
Volume of volumetric flask for each buffer solution: 200 mL
Sampling times and temperature of the oven:
⋅ 0, 17, 19, 21, 23, 41, 43 and 47 hours.

- Sampling intervals/times for sterility check: N/A
- Sample storage conditions before analysis: N/A
- Other observation, if any (e.g.: precipitation, color change etc.): No significant pH changes, all solutions were colorless.

Buffers:

pH 4.0, 7.0 and 9.0
The three buffer solutions (pH 4.0, 7.0 and 9.0) were prepared using Titrisol reagents (Merck) with a precision of 0.1 pH units for each solution. The batch numbers of the reagents were:
⋅ pH 4.0: 0C112733, 0C267163,
⋅ pH 7.0: 0C129522, 0C265097,
⋅ pH 9.0: 00449130, 0C248419.
The water used for the tests was deionised water, prepared at CIT using a Milli-Q apparatus (Millipore).

pH 1.2
Hydrochloride acid at 0.2 N (64.5 mL, Prolabo, ref: 32050602, batch No. X01166) and potassium chloride at 0.2 N (50 mL, Aldrich, ref 31,930-9, batch No. 01322JS) were transferred into a volumetric flask (200 mL) and made to volume with Milli-Q water (Millipore).

Buffer solutions at pH 4.0, 7.0, and 9.0 were prepared. The pH of each buffer solution was checked before use and was degassed using nitrogen (5 minutes). For each buffer solution, one replicate was performed in which an aliquot of the test item was dissolved in a volumetric flask of the buffer solution in a test flask protected from light. A sample (4 mL) of each prepared solution was extracted with n-heptane (2 mL) and analyzed in duplicate with a two-fold dilution in Internal Standard Solution (dodecane, Aldrich, D22, 110-4 at 10 mg/L) in order to determine the initial concentration of the
test item. For each buffer solution, the solution was placed in an oven at specified temperature (temperature was recorded during the test). For each sampling time, the pH value of the solutions was measured, the visual appearance of the solutions noted and samples (4 mL) of each prepared solution were extracted with n-heptane (2 mL) and analyzed in duplicate with a two-fold dilution in Internal Standard Solution.

Estimation method (if used):

Arrhenius plot of Ln k versus 1/T ( T expressed in Kelvin) was constructed from the data in different tests. The values of the Kobs and the t1/2 at 25 deg C for each pH were obtained by extrapolation.

Details on test conditions:

TEST SYSTEM
- Type, material and volume of test flasks, other equipment used: see buffer section
- Sterilisation method: The test was performed under sterile conditions, method not specified.
- Lighting: protected from light
- Measures taken to avoid photolytic effects: not specified.
- Measures to exclude oxygen: N/A
- Details on test procedure for unstable compounds: N/A
- Details of traps for volatile, if any: N/A
- If no traps were used, is the test system open: N/A
- Is there any indication of the test material adsorbing to the walls of the test apparatus? No
TEST MEDIUM
- Volume used/treatment: Varies by pH
- Kind and purity of water: Milli-Q water
- Preparation of test medium: see Buffers section above
- Renewal of test solution: N/A
- Identity and concentration of co-solvent: N/A
OTHER TEST CONDITIONS
- Adjustment of pH: None
- Dissolved oxygen: N/A

Number of replicates:

2 for each buffer

Positive controls:

no

Negative controls:

no

Statistical methods:

The calibration curve was obtained by linear regression analysis of ratio test item peak area/Internal Standard peak area versus concentration. The test item peak area was determined for each sample and the concentration of MMP in each sample was calculated using the equation obtained from the calibration data.

Results and discussion

Preliminary study:

The determination was performed in vessels protected from light. No significant variation of pH was observed for any buffer at any time. Resulting solutions at the end of the test were colorless. The results showed that after 3 days, MMP was hydrolyzed in conditions of pH tested at 50 ± 1 deg. C. In accordance with the guidelines, the investigations were continued at each pH since more than 10% after 3 days but less than 50% was hydrolyzed after 2.4 hours.

Test performance:

MMP was considered hydrolytically unstable. As the boiling point of test item is 54-55 deg. C, the hydrolysis rate was then determined at two different temperatures (27 deg. C and 37 deg. C) for each buffer and one temperature (37 deg. C) for pH = 1.2. The determination was performed to cover approximately 20-70% hydrolysis.

The results of this test indicated a pseudo-first order reaction kinetic.

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

- Formation and decline of each transformation product during test: N/A
- Pathways for transformation: N/A
- Other: N/A

Dissipation DT50 of parent compound

Dissipation DT50 of parent compound 1

pH:

4

Temp.:

25 °C

Hydrolysis rate constant:

0 h-1

DT50:

1 770 h

Type:

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

Remarks on result:

other: estimation

Dissipation DT50 of parent compound 2

pH:

7

Temp.:

25 °C

Hydrolysis rate constant:

0.001 h-1

DT50:

482 h

Type:

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

Remarks on result:

other: estimation

Dissipation DT50 of parent compound 3

pH:

9

Temp.:

25 °C

Hydrolysis rate constant:

0.016 h-1

DT50:

43.6 h

Type:

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

Remarks on result:

other: estimation

Dissipation DT50 of parent compound 4

pH:

1.2

Temp.:

37 °C

Hydrolysis rate constant:

0.019 h-1

DT50:

35.8 h

Type:

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

Other kinetic parameters:

N/A

Details on results:

TEST CONDITIONS
- pH, sterility, temperature, and other experimental conditions maintained throughout the study: Yes
- Anomalies or problems encountered (if yes): N/A

Applicant's summary and conclusion

Validity criteria fulfilled:

yes

Conclusions:

Following advanced tests results, MMP can be considered hydrolytically unstable with: hydrolysis rate constant (Kobs) = 0.000391 h-1 and t½ = 1770 h at 25 deg. C for pH 4.0 (estimation), Kobs = 0.00144 h-1 and t½ = 482 h at 25 deg. C for pH 7.0 (estimation), Kobs = 0.0159 h-1 and t½ = 43.6 h at 25 deg. C for pH 9.0 (estimation), Kobs = 0.0194 h-1 and t½ = 35.8 h at 37 deg. C for pH 1.2.

Executive summary:

N/A