A mixture mainly based on: 2,3-dihydro-6-(2-hydroxy-2-methyl-1-oxopropyl)-1,1,3-trimethyl-3-[4-(2-hydroxy-2-methyl-1-oxopropyl)phenyl]-1H-indene; 2,3-dihydro-5-(2-hydroxy-2-methyl-1-oxopropyl)-1,1,3-trimethyl-3-[4-(2-hydroxy-2-methyl-1-oxopropyl)phenyl]-1H-indene

Hydrolysis

Link to relevant study record(s)

Reference

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

key study

Study period:

03 April 2018 - 18 May 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 111 (Hydrolysis as a Function of pH)

Version / remarks:

2004

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

Test substance: Synacure-150
Molecular mass: 408.54 g·mol-1
Molecular formula: C26H32O4

Radiolabelling:

no

Analytical monitoring:

no

Details on sampling:

The hydrolysis of Synacure-150 was studied in buffer solutions at pHs 4, 7 and 9.
The concentration of the active ingredient was determined by LC/MS immediately after the preparation of the solution, and subsequently samples were incubated at 25, 35 and 50°C for a period of 30 days.
The samples were taken at the following timepoints:
0, 2, 7, 12, 15, 20, 25 and 30 days.

A sterility confirmation test was conducted at the end of the experiment.

Buffers:

Buffer solution Composition Buffer

pH 4 Potassium biphthalate monobasic. Phthalate buffer
pH 7 Potassium dihydrogen phosphate and sodium hydroxide. Phosphate buffer
pH 9 Boric acid, potassium chloride and sodium hydroxide. Borate buffer
pH 10 Boric acid, potassium chloride and sodium hydroxide. Borate buffer

Details on test conditions:

ELIMINATING OXYGEN

In order to eliminate oxygen, nitrogen was bubbled for a period of about 5 minutes, in ultrapure water and buffer solutions, before sterilization of the solutions. Each solution used in this study (as described below) were prepared in a laminar flow chamber, in order to minimize the risk of microbial contamination of the solutions.

SOLVENTS AND BUFFER SOLUTIONS

pHs 4, 7, 9 and 10 sterilized buffers (buffer solution of pH 10 was used only for calibration of pHmeter);

Ultrapure water (sterilized);
Acetic acid Purity: 100%;
Ammonium acetate Purity: 97%;
Acetonitrile HPLC grade Purity: 99.9%;

(TSA)Tryptone Soya Agar;
(SAB) Sabouraud Dextrose Agar;

Duration:

30 d

pH:

4

Temp.:

25 °C

Initial conc. measured:

1.361 mg/L

Duration:

30 d

pH:

4

Temp.:

35 °C

Initial conc. measured:

1.434 mg/L

Duration:

30 d

pH:

4

Temp.:

50 °C

Initial conc. measured:

1.456 mg/L

Duration:

30 d

pH:

7

Temp.:

25 °C

Initial conc. measured:

1.402 mg/L

Duration:

30 d

pH:

7

Temp.:

35 °C

Initial conc. measured:

1.423 mg/L

Duration:

30 d

pH:

7

Temp.:

50 °C

Initial conc. measured:

1.35 mg/L

Duration:

30 d

pH:

9

Temp.:

25 °C

Initial conc. measured:

1.419 mg/L

Duration:

30 d

pH:

9

Temp.:

35 °C

Initial conc. measured:

1.535 mg/L

Duration:

30 d

pH:

9

Temp.:

50 °C

Initial conc. measured:

1.538 mg/L

Number of replicates:

4 replicates per temperature per pH

Positive controls:

no

Negative controls:

no

Statistical methods:

See calculations in 'any other infromation'

Preliminary study:

It was found during the preliminary test, that the concentration of the active ingredient was greater than 10% relative to its initial concentration for pHs 4, 7 and 9. In this case, it is necessary the conduction of the definitive test, since results of the preliminary test indicated that the test substance is unstable, with an estimated half-life less than one year (t½ > 1 year).

Transformation products:

not measured

Remarks:

The item "Identification of hydrolysis products (Tier 3)" from the OECD Guideline 111 (2004) was not performed due to a request of the sponsor.

pH:

4

Temp.:

25 °C

DT50:

43.83 d

Type:

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

pH:

4

Temp.:

35 °C

DT50:

34.51 d

Type:

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

pH:

4

Temp.:

50 °C

DT50:

20.12 d

Type:

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

pH:

7

Temp.:

25 °C

DT50:

44.31 d

Type:

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

pH:

7

Temp.:

35 °C

DT50:

44.28 d

Type:

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

pH:

7

Temp.:

50 °C

DT50:

49.36 d

Type:

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

pH:

9

Temp.:

25 °C

DT50:

40.2 d

Type:

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

pH:

9

Temp.:

35 °C

DT50:

23.43 d

Type:

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

pH:

9

Temp.:

50 °C

DT50:

18.25 d

Type:

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

Details on results:

TEST CONDITIONS
pH, sterility, temperature, and other experimental conditions maintained throughout the study: Yes, see attached background material

For full data tables and calibration curves see attached background material.

Validity criteria fulfilled:

yes

Conclusions:

At pHs 4, 7 and 9, the test substance showed to be unstable at 25, 35 and 50°C with half-lives of less than one year. The half-lives were 43.83 days at 25°C, 34.51 days at 35°C and 20.12 days at 50°C for pH 4. For pH 7 the half-lives were 44.31 days at 25°C, 44.28 days at 35°C and 49.36 days at 50°C and for pH 9 the values were 40.20 days at 25°C, 23.43 days at 35°C and 18.25 days at 50°C.

Executive summary:

It was found during the preliminary test, that the concentration of the active ingredient was greater than 10% relative to its initial concentration for pHs 4, 7 and 9. In this case, it is necessary the conduction of the definitive test, since results of the preliminary test indicated that the test substance is unstable, with an estimated half-life less than one year (t½ > 1 year). The hydrolysis of Synacure-150 was studied in buffer solutions at pHs 4, 7 and 9. The concentration of the active ingredient was determined by LC/MS immediately after the preparation of the solution, and subsequently samples were incubated at 25, 35 and 50°C for a period of 30 days.  

The hydrolysis of Synacure-150 showed to be unstable at 25, 35 and 50°C, with half-life less than one year. The half-lives were 43.83 days at 25 °C, 34.51 days at 35°C and 20.12 days at 50°C for pH 4. For pH 7 the half-lives were 44.31 days at 25°C, 44.28 days at 35°C and 49.36 days at 50°C and for pH 9 the values were 40.20 days at 25°C, 23.43 days at 35°C and 18.25 days at 50°C.

Key value for chemical safety assessment

Half-life for hydrolysis:

9 999 h

at the temperature of:

50 °C