Hydroxyprogesterone

Hydrolysis

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

hydrolysis

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because the substance is readily biodegradable

Conclusions:

Hydroxyprogesteron does not contain functional groups which are susceptible to hydrolytic degradation. Hydrolytic stability is thus to be expected.

Executive summary:

Hydroxyprogesteron does not contain functional groups which are susceptible to hydrolytic degradation. Hydrolytic stability is thus to be expected. This notion is experimentally supported by the results of a hydrolysis study with 1,2-Methylen-4,6-dien (CAS. 2098-65-9) which is structurally similar to hydroxyprogesteron.

Reference 2

Endpoint:

hydrolysis

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Justification for type of information:

Data from structural analog substance 1,2-Methylen-4,6-dien (CAS 2098-65-9)

Reason / purpose for cross-reference:

read-across source

Transformation products:

not specified

% Recovery:

100.2

pH:

4

Temp.:

50 °C

Duration:

5 d

% Recovery:

101.8

pH:

7

Temp.:

50 °C

Duration:

5 d

% Recovery:

98.1

pH:

9

Temp.:

50 °C

Duration:

5 d

Key result

pH:

4

Temp.:

25 °C

DT50:

> 1 yr

Remarks on result:

other: stable

Key result

pH:

7

Temp.:

25 °C

DT50:

> 1 yr

Remarks on result:

other: stable

Key result

pH:

9

Temp.:

25 °C

DT50:

> 1 yr

Remarks on result:

other: stable

Details on results:

"Stable" signifies that less than 10 % of 1,2-methylen-4,6-dien were degraded at the respective pH value during 5 days at 50 °C, corresponding to a half-live > 1 year at 25 °C.

Executive summary:

Hydroxyprogesterone does not contain functional groups which are susceptible to hydrolytic degradation. Hydrolytic stability is thus to be expected. This notion is experimentally supported by the results of a hydrolysis study with 1,2-Methylen-4,6-dien (CAS. 2098-65-9) which is structurally similar to hydroxyprogesterone and was found to be hydrolytically stable (half-life > 1 yr) in pH region 4 - 9 at 25 °C.

Reference 3

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1997

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Justification for type of information:

For hydroxyprogesterone read-across from hydrolysis study of 1,2-methylen-4,6-dien (CAS 2098-65-9), which differs in a methylene group and a double bond, is possible.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method C.7 (Degradation: Abiotic Degradation: Hydrolysis as a Function of pH)

Deviations:

no

GLP compliance:

yes

Remarks:

Draft report

Radiolabelling:

no

Analytical monitoring:

not specified

Details on sampling:

- Sampling time of the hydrolysis solutions at pH 4, 7 and 9: 0, 24, 48 and 120 hrs
- Sampling time of the pH values: at start of incubation and at the end of the hydrolysis experiment

Buffers:

BUFFER SOLUTIONS:
I. 0.05 M acetate buffer solution pH 4:
- 0.74 g (0.009 mole sodium acetate p.a. Merck Art. 6268 (82.03 g/mol) and 2.4 ml (0.042 mole acetic acid 100% p.a. Merck Art. 63 E (60.05 g/mol, density 1.05 g/ml) were dissolved to 1000 ml with double distilled water
- The pH value was adjusted to 4 by adding 0.1 M hydrochloric acid Titrisol (Merck Art. 9973)

II. 0.05 M phosphate buffer solution pH 7:
- 4.34 g (0.031 mole disodium hydrogen phosphate Merck Art. 106566 (141 .96 g/mol) and 2.64 g (0.019 mole potassium dihydrogen phosphate Merck Art. 4881 (136.09 g/mol) were dissolved to 1 000 ml with double distilled water
- The pH value was adjusted to 7 by adding 0.1 M hydrochloric acid Titrisol (Merck Art. 9973)

III. 0.05 M borate buffer solution pH 9:
- 4.78 g (0.012 mole disodium tetraborate Merck Art. 6315 (381 .37 g/mol) and 46 ml (0.0046mole hydrochloric acid Titrisol Merck Art. 9944 (36.46 g/mol) were dissolved to 1000 mL with double distilled water
- As the pH value of borate buffer solutions decreases with increasing temperature, the pH value was adjusted to 9.2 at 25 °C with 1 M sodium hydroxide solution to obtain a pH value of 9.00 at 50 °C.

IV: For calibration of pH meter and electrode:
- standard buffer solutions: pH 4 (Art. 33543}, pH 7 (Art. 33546} and pH 9 (Art. 33548), Riedel-de Haen

Details on test conditions:

EXPERIMENTAL DESIGN:
I. PREPARATION OF THE TEST SOLUTIONS:
- Three test solutions, buffered to pH values of 4, 7 and 9, each with a test concentration of approx. 1 mg/L, were prepared by adding a stock solution in acetonitrile to the corresponding buffer solution which had been equilibrated at 50 °C for one hour, followed by purging with nitrogen to remove dissolved oxygen
- All experiments were conducted using sterilized equipment and buffer solutions

II. TEST PROCEDURE:
- Aliquots of the test solutions were filled into three sterilized 5 ml autosampler vials which were tightly closed with screw caps
- The initial test concentration was measured in triplicate on the test solutions of pH 4, 7 and 9
- The pH values in aliquots of the test solutions were then measured in a separate vessel at 50 °C
- The vials were incubated in a thermostatic water bath at 50± 0.1 °C
- During the incubation 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
- At each sampling time aliquots of each vessel were analyzed by HPLC

Duration:

5 d

pH:

9

Temp.:

50 °C

Initial conc. measured:

1.019 mg/L

Duration:

5 d

pH:

4

Temp.:

50 °C

Initial conc. measured:

1.016 mg/L

Duration:

5 d

pH:

7

Temp.:

50 °C

Initial conc. measured:

1.01 mg/L

Number of replicates:

The initial concentration of the test substance was measured in triplicate on the test solutions of pH 4, 7 and 9.

Positive controls:

no

Negative controls:

no

Transformation products:

no

% Recovery:

100.2

pH:

4

Temp.:

50 °C

Duration:

5 d

% Recovery:

101.8

pH:

7

Temp.:

50 °C

Duration:

5 d

% Recovery:

98.1

pH:

9

Temp.:

50 °C

Duration:

5 d

Key result

pH:

4

Temp.:

25 °C

DT50:

> 1 yr

Remarks on result:

other: stable

Key result

pH:

7

Temp.:

25 °C

DT50:

> 1 yr

Remarks on result:

other: stable

Key result

pH:

9

Temp.:

25 °C

DT50:

> 1 yr

Remarks on result:

other: stable

Details on results:

"Stable" signifies that less than 10 % of the test substance were degraded at the respective pH value during 5 days at 50 °C, corresponding to a half-live > 1 year at 25 °C.

Validity criteria fulfilled:

yes

Conclusions:

1,2-Methylen-4,6-dien was found to be hydrolytically stable in the pH region 4-9 and 25 °C.

Executive summary:

The rate of hydrolysis in aqueous solutions buffered to pH values of 4, 7 and 9 was studied according to Testing Guideline C.7 of the European Community. No hydrolytic degradation was observed within 5 days at pH 4 and 7 at 50 ± 0.1 °C. Less than 10 % hydrolysis occured at pH 9 at pH 4 and 7 within 5 days at 50 ± 0.1 °C. 1,2-Methylen-4,6-diene is hydrolytically stable at pH 4, 7 and 9 and 25 °C.

Description of key information

In accordance with column 2 of REACH annex VIII hydrolysis does not have to be conducted as hydroxyprogesterone is readily biodegradable. Furthermore, it does not contain functional groups, which are susceptible to hydrolytic degradation. Hydrolytic stability is thus to be expected.

Additional information

This notion is experimentally supported by the results of a hydrolysis study with 1,2-Methyen-4,6-dien (CAS 2090 -65 -9) which is structurally similar to hydroxyprogesterone. No hydrolytic degradation was observed within 5 days at pH 4 and 7 at 50 ± 0.1 °C. Less than 10 % hydrolysis occured at pH 4, 7 and 9 within 5 days at 50 ± 0.1 °C. Therefore 1,2 -Methylen-4,6-dien can be considered as hydrolytically stable at pH 4, 7 and 9 and 25 °C.