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Diss Factsheets

Administrative data

Endpoint:
hydrolysis
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2002-04-18 to 2002-11-29
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report date:
2002

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method C.7 (Degradation: Abiotic Degradation: Hydrolysis as a Function of pH)
Version / remarks:
no version available
Deviations:
no
Principles of method if other than guideline:
At pH values where more than 10 % degradation was observed under the conditions of the preliminary test (5 days at 50 °C), experiments at elevated temperatures were necessary in order to extrapolate from the hydrolysis rate constants determined at elevated temperatures to the hydrolysis rate constant at 25 °C. Those experiments were conducted only at one elevated temperature instead of two elevated temperatures. This is justified since acceptable results were obtained.
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
5,6 beta-Epoxy-7 beta-hydroxy-15 beta,16 beta-methylene-3 beta-pivaloyloxy-5 beta-androstan-17-one
EC Number:
617-351-6
Cas Number:
82544-13-6
Molecular formula:
C25 H36 O5
IUPAC Name:
5,6 beta-Epoxy-7 beta-hydroxy-15 beta,16 beta-methylene-3 beta-pivaloyloxy-5 beta-androstan-17-one
Radiolabelling:
no

Study design

Analytical monitoring:
yes
Buffers:
- pH: 4
- Type and final molarity of buffer: 0.05 M
- Composition of buffer: 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. As the pH value of acetate buffer solutions decreases with increasing temperature), the pH value had to be adjusted to 3.96 at 25 °C in order to obtain a pH value of 4.00 at 50 °C. For the experiment at 80 °C, the pH value had to be adjusted to 3.85 at 25 °C. The pH value was adjusted with acetic acid.

- pH: 7
- Type and final molarity of buffer: 0.05 M
- Composition of buffer: 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. The pH value was adjusted to 7 by adding 0.1 M sodium hydroxide solution (Titrisol Merck Art. 109959).

- pH: 9
- Type and final molarity of buffer: 0.05 M
- Composition of buffer: 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. As the pH value of borate buffer solutions decreases with increasing temperature), the pH value had to be adjusted to 9.2 at 25 °C in order to obtain a pH value of 9.00 at 50 °C. For the experiment at 80 °C, the pH value had to be adjusted to 9.44 at 25 °C. The pH value was adjusted with 0.1 M sodium hydroxide solution.
Details on test conditions:
TEST SYSTEM
- Measures taken to avoid photolytic effects: During the incubation of the test solutions in the thermostatic water bath possible photolytic degradation of the test substance was prevented by exclusion of light from the hydrolysis solutions by using a thermostatic bath made of stainless steel with a metal cover.

TEST MEDIUM
- Preparation of test medium: Test solutions with concentrations of approx. 0.3 mg/L in 0.05 M buffer solution pH 4, 7 and 9with 10 % acetonitrile were prepared by adding a stock solution of ZK 90346 in acetonitrile to the corresponding buffer solution in autosampler vials. All buffer solutions had been purged with nitrogen to remove dissolved oxygen. In order to avoid adsorption to surfaces, the vials and caps were pre-rinsed with the hydrolysis solutions, the rinsing solutions discarded and the solutions prepared again in the same vials.
Duration of testopen allclose all
Duration:
598.7 h
pH:
9
Temp.:
50 °C
Initial conc. measured:
0.305 mg/L
Duration:
24 h
pH:
4
Temp.:
80 °C
Initial conc. measured:
0.274 mg/L
Duration:
140.5 h
pH:
4
Temp.:
50 °C
Initial conc. measured:
0.336 mg/L
Duration:
140.6 h
pH:
7
Temp.:
50 °C
Initial conc. measured:
0.277 mg/L
Duration:
45 h
pH:
9
Temp.:
80 °C
Initial conc. measured:
0.282 mg/L
Positive controls:
no
Negative controls:
no

Results and discussion

Preliminary study:
Less than 10 % of the test substance were degraded within 5 days at 50 °C at pH 7. Therefore ZK 90346 can be considered hydrolytically stable at pH 7 and no further experiments were necessary. Since more than 10 % decay was observed at pH 4 and 9 within 5 days at 50 °C, hydrolysis experiments at elevated temperatures were necessary for those two pH values. Therefore additional experiments were conducted at 80 °C.
Transformation products:
yes
Identity of transformation productsopen allclose all
No.:
#1
Reference
Reference substance name:
Unnamed
IUPAC name:
[(3S,5S,7S,11R,14S,16R,17R,18R)-16,17,18-trihydroxy-7,11-dimethyl-6-oxo-14-
pentacyclo[8.8.0.02,7.03,5.011,16]octadecanyl] 2,2-dimethylpropanoate
Molecular formula:
C25H38O6
Molecular weight:
434.57
SMILES notation:
CC(C)(C)C(=O)O[C@H]1CC[C@]2(C)C3CC[C@@]4(C)C([C@@H]5C[C@@H]5C4=O)
C3[C@@H](O)[C@@H](O)[C@@]2(O)C1
No.:
#2
Reference
Reference substance name:
Unnamed
IUPAC name:
(2R,5S,7S,9R,10R,13S,15S,17S)-5,10-dihydroxy-2,17-dimethyl-8-oxahexacyclo[9.8.0.02,7.07,9.012,17.013,15
nonadecan-16-one
CAS number:
n.a.
Molecular formula:
C20H28O4
Molecular weight:
332.43
SMILES notation:
C[C@]12CCC3C([C@@H](O)[C@H]4O[C@]45C[C@@H](O)CC[C@]35C)C1[C@@H]6C[C@@H]6C2=O
Details on hydrolysis and appearance of transformation product(s):
Two functional groups in ZK 90346 give rise to two different hydrolysis reactions: the epoxide is cleaved at acidic pH values and the ester is hydrolyzed at alkaline pH values. The hydrolysis product at acidic pH values is the trans-diol ZK 152258. It can be identified by a peak at 6.8 min in the HPLC diagrams of the hydrolysis solutions at pH 4 increasing with hydrolysis time. At alkaline pH values the free alcohol is the hydrolysis product. Due to the very low concentration of the hydrolysis solutions and the low UV absorbance of the product, it could not be identified in the HPLC diagrams.
Dissipation DT50 of parent compoundopen allclose all
Key result
pH:
9
Temp.:
25 °C
Type:
not specified
Remarks on result:
hydrolytically stable based on preliminary test
Key result
pH:
7
Temp.:
25 °C
Type:
not specified
Remarks on result:
hydrolytically stable based on preliminary test
Remarks:
stabel at pH 7 and 9 at 25°C

Applicant's summary and conclusion

Validity criteria fulfilled:
yes
Executive summary:

The rate of hydrolysis of ZK 90346 was determined at pH 4, 7 and 9. The rate constants and half-lives at 25 °C are:

 pH  k [1/h]  95 % confidence intervals for k [1/h]  t1/2  95 % confidence intervals for t1/2
 4  1.738 E-03  1.099 E-03 to 2.377 E-03  17 d  12 to 26 d
 7  -  -  stable*  -
 9  6.414 E-05  4.967 E-05 to 7.860 E-05  1.2 a*  1.0 to 1.6 a

* according to criterion in EC guideline C.7 (half-life > 1 year at 25 °C) the test substance is to be considered stable at pH 7 and 9, 25 °C