Methanesulfonamide, N-[2-[(4,6-dimethoxy-1,3,5-triazin-2-yl)carbonyl]-6-fluorophenyl]-1,1-difluoro-N-methyl-

Hydrolysis

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP Guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 111 (Hydrolysis as a Function of pH)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 835.2130 (Hydrolysis as a Function of pH and Temperature)

Qualifier:

according to guideline

Guideline:

other: Canada PMRA Environmental Chemistry and Fate Guideline

Qualifier:

according to guideline

Guideline:

other: Japan MAFF Test Guideline, 12 Nousan 8147

Qualifier:

according to guideline

Guideline:

other: EU Directives 94/37/EC and 95/36/EC

GLP compliance:

yes (incl. QA statement)

Remarks:

Ministerium für Arbeit, Gesundheit und Soziales des Landes Nordrhein-Westfalen

Radiolabelling:

yes

Analytical monitoring:

yes

Details on sampling:

- Sampling intervals for the parent/transformation products:
Test 1 (Pre-test):
0, 2, 4, 7 days at pH 4;
0, 1, 2, 3, 4, 7, 9 days at pH 7;
0, 1, 1.5, 2, 2.5, 3, 3.5, 6 hours at pH 9.
Test 2 (Main test):
0, 3, 7, 10, 14, 21, 30 days at pH 7;
0, 0.25, 1, 2, 4, 7, 10, 14, 21, 30 days at pH 9.
Test 3 (Optional test):
0, 3, 7, 10, 14, 21, 30 days at pH 7;
0, 1, 2, 4, 7, 10, 14, 21, 30 days at pH 9.
- Sampling method: Two replicates were removed from the water bath at each interval for each pH
- Sampling intervals/times for pH measurements: At each sampling interval in each test
- Sampling intervals/times for sterility check: At each sampling interval in for the first replicates of each test
- Other observation, if any (e.g.: precipitation, color change etc.): None

Buffers:

The tests were performed in solutions buffered at pH levels of 4, 7, and 9 (acetate, TRIS, and borate buffers):

- pH: 4
- Type and final molarity of buffer: Acetate, 0.01 M
- Composition of buffer: Stock solution pH 4 (0.04 M): 1.36 g CH3COONa x 3 H2O was dissolved in a volume of 250 mL water. The pH of that solution was measured with a pH electrode and then adjusted to pH 4.0 at the respective temperature (50°C, 25°C or 20°C) using acetic acid.The buffer stock solution was diluted to the desired 0.01 mol/L with purified water (1/3, v/v).

- pH: 7
- Type and final molarity of buffer: TRIS, 0.01 M
- Composition of buffer: 1.21 g tris(hydroxymethyl)-aminomethane was mixed with 46.6 mL of a 0.1 N aqueous hydrochloric acid solution (3.65 g HCl/L H2O) and diluted to 800 mL with purified water. The pH of this solution was measured with a pH electrode and then adjusted to pH 7.0 at the respective temperature (50°C, 25°C or 20°C) using 0.1 N aqueous hydrochloric acid solution and/or 0.1 N aqueous sodium hydroxide solution, respectively.

- pH: 9
- Type and final molarity of buffer: Borate, 0.01 M
- Composition of buffer: Stock solution pH 9 (0.02 M): 0.62 g boric acid (H3BO3) and 0.75 g of KCl were dissolved in 250 ml water. To an aliquot of 125 mL of that solution 53 mL of a 0.04 N aqueous sodium hydroxide solution (1.6 g NaOH/L H2O) was added and diluted with water to a total volume of 250 mL. The pH of this solution was measured with a pH electrode and then adjusted to pH 9.0 at the respective temperature (50°C, 30°C or 25°C) using 0.4 N sodium hydroxide solution and/or boric acid, respectively.The buffer stock solution was diluted to the desired 0.01 mol/L with purified water (1/1, v/v).

Details on test conditions:

TEST SYSTEM
- Type, material and volume of test flasks, other equipment used: 10-mL glass crimp-top vials closed with Teflon®-faced septa and placed in a temperature-controlled water bath.
- Sterilisation method: Steam pressure sterilization
- Lighting: dark

TEST MEDIUM
- Volume used/treatment: 5 mL
- Kind and purity of water: deionized, ultrapure
- Identity and concentration of co-solvent: Acetonitrile, approximately 0.1%.

Duration:

7 d

pH:

4

Temp.:

50 °C

Initial conc. measured:

1 - 1.1 mg/L

Duration:

9 d

pH:

7

Temp.:

50 °C

Initial conc. measured:

1 - 1.1 mg/L

Duration:

6 h

pH:

9

Temp.:

50 °C

Initial conc. measured:

1 - 1.1 mg/L

Duration:

30 d

Temp.:

25 °C

Initial conc. measured:

1 - 1.1 mg/L

Duration:

30 d

Temp.:

20 °C

Initial conc. measured:

1 - 1.1 mg/L

Number of replicates:

Two replicates were removed from the water bath at each interval for each pH.

Statistical methods:

Arithmetic means were used for all LS measurements.

Preliminary study:

DT50 at pH4 and 50°C no calculation, less than 10% degradation after 5 days.
DT50 at pH7 and 50°C = 4.6 days
DT50 at pH9 and 50°C = 1.8 hours

Transformation products:

yes

No.:

#1

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

Especially at pH values above 7, the compound was thoroughly hydrolyzed to AE 1887196-O-desmethyl. Identified by HPLC-MS(/MS).

% Recovery:

99.6 - 102

St. dev.:

1.5

pH:

7

Temp.:

25 °C

Duration:

0 - 30 d

% Recovery:

99.9 - 101.8

St. dev.:

1.5

pH:

9

Temp.:

25 °C

Duration:

0 - 30 d

pH:

7

Temp.:

25 °C

DT50:

118 d

Type:

other: Single First Order Kinetics

Remarks on result:

other: Chi2 Error = 0.9 %; DT90 = 392 days

pH:

9

Temp.:

25 °C

DT50:

2.4 d

Type:

other: Single First Order Kinetics

Remarks on result:

other: Chi2 Error = 0.6 %; DT90 = 8.1 days

Details on results:

TEST CONDITIONS
- pH, sterility, temperature, and other experimental conditions maintained throughout the study: Yes
- Anomalies or problems encountered (if yes): No

MATERIAL BALANCE
Mean material balances ranged from 95.1 to 103.6% of the applied radioactivity [% AR] for all solutions.
The complete material balances found at all sampling intervals demonstrated that there was no significant loss of radioactivity from the test systems or during sample processing.

VOLATILIZATION
Since the test systems were sealed and a loss in material balance was not observed, no attempt was made to trap volatiles.

MAJOR TRANSFORMATION PRODUCTS
One degradation product ≥ 10% AR was detected and identified as AE 1887196-O-desmethyl.

The results show that the hydrolytic degradation under sterile conditions is strongly depends on the temperature and the pH value. Under typical conditions in the aquatic environment the substance will hydrolyse slowly. The DT50 values at pH 7 were 118 and 204 days at 25 and 20 °C, respectively. One degradation product ≥ 10% AR was detected and identified as AE 1887196-O-desmethyl. 

Table 1: Summary of results according to single first order kinetics:

	pH	DT50 [days]	DT90 [days]	Chi2 Error [%]
Test 1 / 50°C	4	No calculation, less than 10% degradation after 5 days.
Test 1 / 50°C	7	4.6	15.1	1.9
Test 1 / 50°C	9	1.8 hours	6.0 hours	2.1
Test 2 / 25°C	7	118	392	0.9
Test 2 / 25°C	9	2.4	8.1	0.6
Test 3 / 20°C	7	204	676	0.4
Test 3 / 20°C	9	4.8	16.0	3.8

Reference 2

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP Guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 111 (Hydrolysis as a Function of pH)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 835.2130 (Hydrolysis as a Function of pH and Temperature)

Qualifier:

according to guideline

Guideline:

other: Commission Directives 94/37/EC and 95/36/EC amending Council Directive 91/414/EEC

Qualifier:

according to guideline

Guideline:

other: Japanese MAFF New Test Guidelines Annex No. 2-6-1

GLP compliance:

yes (incl. QA statement)

Remarks:

Ministerium für Arbeit, Gesundheit und Soziales des Landes Nordrhein-Westfalen

Specific details on test material used for the study:

Details on properties of test surrogate or analogue material (migrated information):
PHYSICO-CHEMICAL PROPERTIES
- Vapour pressure: 6.4 x 10-E6 Pa at 20°C
- Water solubility:
41 mg/L (distilled water, pH 6.8) at 20°C
36 mg/L (buffer, pH 4) at 20°C
33 mg/L (buffer, pH 7) at 20°C
34 mg/L (buffer, pH 9) at 20°C
- log Pow: 1.5 - 1.6
- pKa: no pKa in water at 1.1 < pH < 10.4
- Stability of test material: The analysis with the confirmatory method was performed after a storage period of about five months. The results are comparable with the results obtained with the primary chromatographic method immediately after sampling. This shows that the test item and its transformation products were stable in the respective buffer solutions.

Radiolabelling:

yes

Analytical monitoring:

yes

Details on sampling:

- Sampling intervals for the parent/transformation products:
Test 1 (Pre-test):
0, 2, 4, 7 days at pH 4;
0, 1, 2, 3, 4, 7, 9 days at pH 7;
0, 1, 1.5, 2, 2.5, 3, 3.5, 6 hours at pH 9.
Test 2 (Main test):
0, 3, 6, 10, 14, 22, 30 days at pH 4;
0, 3, 6, 10, 14, 22, 30 days at pH 7;
0, 0.25, 1, 2, 3, 6, 10, 14, 22, 30 days at pH 9.
Test 3 (Optional test):
0, 3, 6, 10, 14, 22, 30 days at pH 7;
0, 0.25, 1, 2, 3, 6, 10, 14, 22, 30 days at pH 9.
- Sampling method: Two replicates were removed from the water bath at each interval for each pH
- Sampling intervals/times for pH measurements: At each sampling interval in each test
- Sampling intervals/times for sterility check: At each sampling interval in for the first replicates of each test
- Sample storage conditions before analysis: max. 1 day (primary method), about 5 months (confirmatory method)
- Other observation, if any (e.g.: precipitation, color change etc.): None

Buffers:

The tests were performed in solutions buffered at pH levels of 4, 7, and 9 (acetate, TRIS, and borate buffers):

- pH: 4
- Type and final molarity of buffer: Acetate, 0.01 M
- Composition of buffer: Stock solution pH 4 (0.04 M): 1.36 g CH3COONa x 3 H2O was dissolved in a volume of 250 mL water. The pH of the solution was measured with a pH electrode and then adjusted to pH 4.0 at the respective temperature (50 °C, 25 °C) using acetic acid. The buffer stock solution was diluted to the desired 0.01 mol/L with purified water (1/3, v/v).

- pH: 7
- Type and final molarity of buffer: TRIS, 0.01 M
- Composition of buffer: 0.30 g tris(hydroxymethyl)-aminomethane was mixed with 11.65 mL of a 0.1 N aqueous hydrochloric acid solution (3.65 g HCl/L H2O) and diluted to 250 mL with purified water. The pH of this solution was measured with a pH electrode and then adjusted to pH 7.0 at the respective temperature (50 °C, 25 °C and 20 °C) using 0.1 N aqueous hydrochloric acid solution and/or 0.1 N aqueous sodium hydroxide solution, respectively.

- pH: 9
- Type and final molarity of buffer: Borate, 0.01 M
- Composition of buffer: Stock solution pH 9 (0.02 M): 0.62 g boric acid (H3BO3) and 0.75 g of KCl were dissolved in 250 ml water. 53 mL 0.04 N aqueous sodium hydroxide solution (1.6 g NaOH/L H2O) were added to 125 mL of the solution and diluted with water to a total volume of 250 mL. The pH of this solution was measured with a pH electrode and then adjusted to pH 9.0 at the respective temperature (50°C, 25°C and 20°C) using 0.4 N sodium hydroxide solution and/or boric acid, respectively. The buffer stock solution was diluted to the desired 0.01 mol/L with purified water (1/1, v/v).

Details on test conditions:

TEST SYSTEM
- Type, material and volume of test flasks, other equipment used: 10-mL glass crimp-top vials closed with Teflon®-faced septa and placed in a temperature-controlled water bath.
- Sterilisation method: Steam pressure sterilization
- Lighting: dark

TEST MEDIUM
- Volume used/treatment: 5 mL
- Kind and purity of water: deionized, ultrapure
- Identity and concentration of co-solvent: Acetonitrile, approximately 0.1%.

Duration:

7 d

pH:

4

Temp.:

50 °C

Initial conc. measured:

1 - 1.1 mg/L

Duration:

9 d

pH:

7

Temp.:

50 °C

Initial conc. measured:

1 - 1.1 mg/L

Duration:

6 h

pH:

9

Temp.:

50 °C

Initial conc. measured:

1 - 1.1 mg/L

Duration:

30 d

Temp.:

25 °C

Initial conc. measured:

1 - 1.1 mg/L

Duration:

30 d

Temp.:

20 °C

Initial conc. measured:

1 - 1.1 mg/L

Number of replicates:

Two replicates were removed from the water bath at each interval for each pH.

Statistical methods:

Arithmetic means were used for all LS measurements.

Preliminary study:

DT50 at pH4 and 50°C = 63.8 days
DT50 at pH7 and 50°C = 4.4 days
DT50 at pH9 and 50°C = 2.1 hours

Transformation products:

yes

No.:

#1

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

Identified by HPLC-MS(/MS) including accurate mass determination after isolation from a pH 9 sample at 25 °C.

% Recovery:

98.4 - 100.2

St. dev.:

0.5

pH:

4

Temp.:

25 °C

Duration:

0 - 30 d

% Recovery:

98.7 - 100.9

St. dev.:

0.5

pH:

7

Temp.:

25 °C

Duration:

0 - 30 d

% Recovery:

97 - 99.2

St. dev.:

0.7

pH:

9

Temp.:

25 °C

Duration:

0 - 30 d

pH:

4

Temp.:

25 °C

DT50:

411 d

Type:

other: Single First Order Kinetics

Remarks on result:

other: Chi2 Error = 0.7 %; DT90 > 1000 days

pH:

7

Temp.:

25 °C

DT50:

153 d

Type:

other: Single First Order Kinetics

Remarks on result:

other: Chi2 Error = 0.5 %; DT90 = 508 days

pH:

9

Temp.:

25 °C

DT50:

2.4 d

Type:

other: Single First Order Kinetics

Remarks on result:

other: Chi2 Error = 3.7 %; DT90 = 8 days

Details on results:

TEST CONDITIONS
- pH, sterility, temperature, and other experimental conditions maintained throughout the study: Yes
- Anomalies or problems encountered (if yes): No

MATERIAL BALANCE
Mean material balances ranged from 98.5 to 101.9% of the applied radioactivity [% AR] for all solutions.
The complete material balances found at all sampling intervals demonstrated that there was no significant loss of radioactivity from the test systems or during sample processing.

VOLATILIZATION
Since the test systems were sealed and a loss in material balance was not observed, no attempt was made to trap volatiles.

MAJOR TRANSFORMATION PRODUCTS
One degradation product ≥ 10% AR was detected and identified as AE 1887196-O-desmethyl. Small amounts of extractable and charaterisable by chromatography residues were observed with no one component exceeding 8.0% AR at any sampling interval.

The results show that the hydrolytic degradation under sterile conditions is strongly depends on the temperature and the pH value. Under typical conditions in the aquatic environment the substance will hydrolyse slowly. The DT50 values at pH 7 were 153 and 280 days at 25 and 20 °C, respectively. One degradation product ≥ 10% AR was detected and identified as AE 1887196-O-desmethyl. 

Table 1: Summary of results according to single first order kinetics:

	pH	DT50 [days]	DT90 [days]	Chi2 Error [%]
Test 1 / 50°C	4	63.8	212	0.4
Test 1 / 50°C	7	4.4	14.7	2.1
Test 1 / 50°C	9	2.1 hours	6.8 hours	0.7
Test 2 / 25°C	4	411	>1000	0.7
Test 2 / 25°C	7	153	508	0.5
Test 2 / 25°C	9	2.4	8.0	3.7
Test 3 / 20°C	7	280	932	0.6
Test 3 / 20°C	9	4.6	15.3	2.0

Description of key information

DT50 at pH7 = 118-280 days (OECD 111)

Triafamone will hydrolyse slowly.

Additional information

Hydrolysis of triafamone (CAS No. 874195-61-6) as a function of pH was investigated according to OECD guideline 111 under GLP conditions (Stroech and Weuthen, 2012; Heinemann, 2012). The hydrolytic degradation was studied in sterile aqueous buffer solutions at pH 4, pH 7 and pH 9 in the dark with a nominal test concentration of 1.0 mg/L for a maximum of 30 days at 50.0, 25.0 and 20.0 °C. Radio labeled [phenyl-UL-14C] Triafamone and [Triazine-UL-14C] Triafamone was used as test substance and the amounts of test item and its degradation products in the solutions were determined by liquid scintillation counting (LSC) and HPLC/radiodetection. Degradation products were identified by HPLC-MS(/MS) including accurate mass determination. One degradation product ≥ 10% was detected and identified as AE 1887196-O-desmethyl. The complete material balances found at all sampling intervals demonstrated that there was no significant loss of radioactivity from the test systems or during sample processing. The results show that the hydrolytic degradation of triafamone under sterile conditions strongly depends on the temperature and the pH value. The DT50 values at pH 7 were 118-153 and 204-280 days at 25 and 20 °C, respectively. Therefore, it can be concluded that triafamone will hydrolyse in pure water slowly under typical environmental aquatic conditions.