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Diss Factsheets

Environmental fate & pathways

Hydrolysis

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Link to relevant study record(s)

Reference
Endpoint:
hydrolysis
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2002
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
according to guideline
Guideline:
EU Method C.7 (Degradation: Abiotic Degradation: Hydrolysis as a Function of pH)
GLP compliance:
no
Specific details on test material used for the study:
21-Acetoxy-6β-fluoro-16α-methyl-4-pregnene-3,20-dione is a mixture of the 6-α- and the 6-ß-isomer (6-α-FM-DOCA and 6-ß-FM-DOCA) in the ratio of approx. 1:1.
Radiolabelling:
no
Analytical monitoring:
yes
Remarks:
HPLC
Details on sampling:
Procedures for incubation and sampling:
- Aliquots of test solutions were filled into sterilized 5 mL autosampler vials which were tightly closed with screw caps
- vials were incubated in a thermostatic water bath at the corresponding test temperature and the temperature was kept constant within ± 0.1 °C
- prior to incubation the initial concentration of 6-α-FM-DOCA and 6-ß-FM-DOCA was measured in triplicate on the test solutions of pH 4, 7 and 9
- possible photolytic degradation of the test substance during the incubation was prevented by exclusion of light from the hydrolysis solutions by using a thermostatic bath made of stainless steel with a metal cover
- at each sampling time two vials from each of the hydrolysis solutions were removed from the thermostatic bath and aliquots of each vessel were analyzed by HPLC
- pH values in aliquots of the test solutions were measured in a separate vessel at the test temperatures at the start of incubation and at each sampling time
- samples were taken at appropiate intervals
Buffers:
Buffer solutions
0.05 M acetate buffer solution pH 4:
-0.657 g = 0.008 mol sodium acetate p.a. Merck Art. 106268 (M = 82.03 g/mol) and 2.4 mL = 0.042 mol acetic acid 100 % p.a. Merck Art. 100063 E (M = 60.05 g/mol, density = 1.05 g/mL) were dissolved to 1000 mL with double distilled water
- pH value was adjusted to 4 by adding acetic acid

0.05 M phosphate buffer solution pH 7:
- 4.34 g = 0.031 mol disodium hydrogen phosphate Merck Art. 106566 (M = 141.96 g/mol) and 2.64 g = 0.019 mol potassium dihydrogen phosphate Merck Art. 105108 (M = 136.09 g/mol) were dissolved to 1000 mL with double distilled water
- pH value was adjusted to 7 by adding 0.1 M sodium hydroxide solution (Titrisol Merck Art. 109959)

0.05 M borate buffer solution pH 9:
- 2.52 g = 0.0125 mol disodium tetraborate Merck Art. 106309 (M = 201.22 g/mol) and 46 mL = 0.0046 mol hydrochloric acid Titrisol Merck Art. 109973 (0.1 M) were dissolved to 1000 mL with double distilled water
- pH value was adjusted to 9.00 by adding 0.1 M sodium hydroxide solution (Titrisol Merck Art. 109959)

buffer solutions for calibration of pH meter:
- standard buffer solutions pH 4 (Art. 33543), pH 7 (Art. 33546) and pH 9 (Art. 33548), Riedel-de Haen
Estimation method (if used):
The rate constant at 25 °C was calculated by using the Arrhenius equation and the experimental data.
Details on test conditions:
Preparation of the test solutions:
- Test solutions with concentrations of approx. 2 mg/L for 6-α-FM-DOCA and 6-ß-FM-DOCA in 0.05 M buffer solution pH 4, 7 and 9 with 1 % acetonitrile were prepared by adding a stock solution of 21-Acetoxy-6β-fluoro-16α-methyl-4-pregnene-3,20-dione in acetonitrile to the corresponding buffer solution
- All buffer solutions had been equilibrated at the corresponding test temperature (with exception of the test at 80 °C) followed by purging with nitrogen to remove dissolved oxygen
- Experiments were conducted using sterilized equipment and buffer solutions
- One test solution was prepared for the experiments at pH 4 and 7, 50 and 80 °C
- Two sets of test solutions were prepared for the experiments at pH 7, 60 °C and pH 9, 25 °C
Duration:
121.5 h
pH:
4.04
Temp.:
50 °C
Initial conc. measured:
2.54 mg/L
Remarks:
6-α-FM-DOCA
Duration:
121.5 h
pH:
4.04
Temp.:
50 °C
Initial conc. measured:
2.09 mg/L
Remarks:
6-ß-FM-DOCA
Duration:
189.5 h
pH:
6.97
Temp.:
50 °C
Initial conc. measured:
2.55 mg/L
Remarks:
6-α-FM-DOCA
Duration:
189.5 h
pH:
6.97
Temp.:
50 °C
Initial conc. measured:
2.08 mg/L
Remarks:
6-ß-FM-DOCA
Duration:
61.2 h
pH:
6.97
Temp.:
60 °C
Initial conc. measured:
2.57 mg/L
Remarks:
6-α-FM-DOCA (solution 1)
Duration:
61.2 h
pH:
6.97
Temp.:
60 °C
Initial conc. measured:
2.13 mg/L
Remarks:
6-ß-FM-DOCA (solution 1)
Duration:
59.8 h
pH:
6.97
Temp.:
60 °C
Initial conc. measured:
2.28 mg/L
Remarks:
6-α-FM-DOCA (solution 2)
Duration:
59.8 h
pH:
6.97
Temp.:
60 °C
Initial conc. measured:
1.89 mg/L
Remarks:
6-ß-FM-DOCA (solution 2)
Duration:
15.9 h
pH:
7
Temp.:
80 °C
Initial conc. measured:
2.56 mg/L
Remarks:
6-α-FM-DOCA
Duration:
15.9 h
pH:
6.99
Temp.:
80 °C
Initial conc. measured:
2.12 mg/L
Remarks:
6-ß-FM-DOCA
Statistical methods:
The software (KIM version 1.0) used for this calculation is based on TopFit 2.0, a multi purpose kinetic data analysis program
Preliminary study:
Due to the presence of an ester function in 21-Acetoxy-6β-fluoro-16α-methyl-4-pregnene-3,20-dione the test substance was expected to be hydrolytically instable at pH 9. Therefore the hydrolysis experiments at this pH value were directly conducted at 25 °C and the preliminary test was only conducted at pH 4 and pH 7 where the hydrolytic behaviour of the test substance was unknown.
Transformation products:
not specified
% Recovery:
99.2
pH:
4.04
Temp.:
50 °C
Duration:
121.5 h
Remarks on result:
hydrolytically stable based on preliminary test
Remarks:
6-α-FM-DOCA
% Recovery:
98.1
pH:
4.04
Temp.:
50 °C
Duration:
121.5 h
Remarks on result:
hydrolytically stable based on preliminary test
Remarks:
6-ß-FM-DOCA
% Recovery:
35.3
pH:
6.97
Temp.:
50 °C
Duration:
189.5 h
Remarks on result:
other:
Remarks:
6-α-FM-DOCA
% Recovery:
15.9
pH:
6.97
Temp.:
50 °C
Duration:
189.5 h
Remarks on result:
other:
Remarks:
6-ß-FM-DOCA
% Recovery:
33.5
pH:
6.97
Temp.:
60 °C
Duration:
61.2 h
Remarks on result:
other:
Remarks:
6-α-FM-DOCA (solution 1)
% Recovery:
15.5
pH:
6.97
Temp.:
60 °C
Duration:
61.2 h
Remarks on result:
other:
Remarks:
6-ß-FM-DOCA (solution 1)
% Recovery:
34.2
pH:
6.97
Temp.:
60 °C
Duration:
59.8 h
Remarks on result:
other:
Remarks:
6-α-FM-DOCA (solution 2)
% Recovery:
15.9
pH:
6.97
Temp.:
60 °C
Duration:
59.8 h
Remarks on result:
other:
Remarks:
6-ß-FM-DOCA (solution 2)
% Recovery:
16
pH:
6.99
Temp.:
80 °C
Duration:
15.9 h
Remarks on result:
other:
Remarks:
6-α-FM-DOCA
% Recovery:
4.7
pH:
6.99
Temp.:
80 °C
Duration:
15.9 h
Remarks on result:
other:
Remarks:
6-ß-FM-DOCA
% Recovery:
10.2
pH:
8.94
Temp.:
25 °C
Duration:
126.1 h
Remarks on result:
other:
Remarks:
6-α-FM-DOCA (solution 1)
% Recovery:
10
pH:
8.94
Temp.:
25 °C
Duration:
126.1 h
Remarks on result:
other:
Remarks:
6-ß-FM-DOCA (solution 1)
% Recovery:
16.3
pH:
8.94
Temp.:
25 °C
Duration:
125.6 h
Remarks on result:
other:
Remarks:
6-α-FM-DOCA (solution 2)
% Recovery:
16.4
pH:
8.94
Temp.:
25 °C
Duration:
125.6 h
Remarks on result:
other:
Remarks:
6-ß-FM-DOCA (solution 1)
pH:
4
Temp.:
25 °C
DT50:
> 1 yr
Remarks on result:
hydrolytically stable based on preliminary test
Remarks:
6-α-FM-DOCA
pH:
4
Temp.:
25 °C
DT50:
> 1 yr
Remarks on result:
hydrolytically stable based on preliminary test
Remarks:
6-ß-FM-DOCA
pH:
7
Temp.:
25 °C
Hydrolysis rate constant:
0.003 h-1
DT50:
109 d
Remarks on result:
other: Arrhenius extrapolation
Remarks:
6-α-FM-DOCA
pH:
7
Temp.:
25 °C
Hydrolysis rate constant:
0.005 h-1
DT50:
57 d
Remarks on result:
other: Arrhenius extrapolation
Remarks:
6-ß-FM-DOCA
pH:
9
Temp.:
25 °C
Hydrolysis rate constant:
0.017 h-1
DT50:
39.6 h
Remarks on result:
other: Arrhenius extrapolation
Remarks:
6-α-FM-DOCA
pH:
9
Temp.:
25 °C
Hydrolysis rate constant:
0.019 h-1
DT50:
36.8 h
Remarks on result:
other: Arrhenius extrapolation
Remarks:
6-ß-FM-DOCA
Details on results:
The hydrolysis rates increased with pH, indicating a base-catalized ester hydrolysis.
Validity criteria fulfilled:
not specified
Conclusions:
21-Acetoxy-6β-fluoro-16α-methyl-4-pregnene-3,20-dione is a mixture of the 6-α- and the 6-ß-isomer (6-α-FM-DOCA and 6-ß-FM-DOCA) in the ratio of approx. 1:1. Accordingly, the rate of hydrolysis for both isomer were determined. The rate of hydrolysis of 6-alpha-FM-DOCA was determined at pH 4, 7 and 9 and the half-lives at 25 °C were in the range between 39.6 hours (pH 9), 109.0 days (pH 7) and higher than one year (pH 4). The rate of hydrolysis of 6-beta-FM-DOCA were in the range between 36.8 hours (pH 9), 57.0 days (pH 7) and higher than one year (pH 4). Thus, 21-Acetoxy-6β-fluoro-16α-methyl-4-pregnene-3,20-dione is considered to be stable at pH 4 at 25 °C.
Executive summary:

21-Acetoxy-6β-fluoro-16α-methyl-4-pregnene-3,20-dione is a mixture of the 6-α- and the 6-ß-isomer (6-α-FM-DOCA and 6-ß-FM-DOCA) in the ratio of approx. 1:1. Therefore the rate of hydrolysis was determined for each of the isomers separately. The rate of hydrolysis in aqueous solutions buffered to pH values of 4, 7 and 9 was studied following the EU Guideline C.7. Due to the presence of an ester function in 21-Acetoxy-6β-fluoro-16α-methyl-4-pregnene-3,20-dione the substance was expected to be hydrolytically instable at pH 9. Therefore the hydrolysis experiments at this pH value were directly conducted at 25 °C. Since the hydrolytic behaviour of the test substance was unknown at pH4 and 7, the preliminary test defined by the guideline (incubation at 50 ± 0.1 °C) was performed to assess whether more than 50 % of the test substance are degraded within 2.4 hours at 50 °C (corresponding to a half-life of less than 24 hours at 25 °C) or if the test substance can be considered hydrolytically stable (less than 10 % hydrolytic degradation within 5 days at 50 °C corresponding to t½ > 1 year at 25 °C). Since more than 10 % of the test substance was degraded at pH 7 within 5 days at 50 ± 0.1 °C, additional hydrolysis experiments had to be conducted at 60 °C and 80 °C. The rate constant at 25 °C was calculated by using the Arrhenius equation and the experimental data. At pH 9, the test solutions were directly incubated at 25 ± 0.1 °C. The half-lives of 6-alpha-FM-DOCA at 25 °C were in the range between 39.7 hours (pH 9), 109.5 days (pH 7) and higher than one year (pH 4). The rate of hydrolysis of 6-beta-FM-DOCA were in the range between 36.9 hours (pH 9), 57.0 days (pH 7) and higher than one year (pH 4). Thus, 21-Acetoxy-6β-fluoro-16α-methyl-4-pregnene-3,20-dione is considered to be stable at pH 4 at 25 °C.

Description of key information

The hydrolytic behaviour of Fluocortolon-A-Acetat is expected to be similar to that of the structurally closely related compound 6-alpha-FM-DOCA, which differs in the missing hydroxy group in position 11 of the steroid moiety, only. The rate of hydrolysis of this compound was determined according to EC guideline C.7 at pH 4, 7 and 9. The compound was found to be hydrolytically stable at pH 4 at 25 °C. Half-lives of hydrolysis of 109 d (101 -118 d) were observed at pH 7 and 39.5 h (37.9 - 41.5 h) at pH 9, which indicate a base catalized ester hydrolysis. Comparable results are to be expected for Fluocortolon-A-acetate.


For a detailed rationale on the analogue approach please refer to IUCLID section 13.

Key value for chemical safety assessment

Half-life for hydrolysis:
39.5 h
at the temperature of:
25 °C

Additional information