D-Glucitol, 1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-, 2,3,4,6-tetrakis(2,2-dimethylpropanoate), (1S)-

Hydrolysis

Link to relevant study record(s)

Reference

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2016-07-13 to 2017-02-24

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 111 (Hydrolysis as a Function of pH)

Deviations:

yes

Remarks:

In the main study at 50°C temperature was controlled within ± 0.6°C instead of 0.5°C. Evaluation: This had no impact on the results.

Qualifier:

according to guideline

Guideline:

EPA OPPTS 835.2120 (Hydrolysis of Parent and Degradates as a Function of pH at 25°C)

Deviations:

no

GLP compliance:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: I15AB0305 and I16LB4607
- Expiration date of the lot/batch: 2017-01-23 (retest date for batch I15AB0305) and 2018-12-18 (retest date for batch I16LB4607)
- Purity test date: 2015-09-22 (certificate release date for batch I15AB0305) and 2017-01-05 (certificate release date for batch I16LB4607)
- Purity: 99.7% (for both batches)

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature

Radiolabelling:

no

Analytical monitoring:

yes

Details on sampling:

- For preliminary test Tier 1: The concentration of the test item in the test samples was determined immediately after preparation (t=0) and after 5 days.
- For main study Tier 2: The concentrations of the test item were determined immediately after preparation (t=0) and at several sampling points after t=0.

Buffers:

-Acetate buffer pH 4, 0.01 M: Solution of 16.7% 0.01 M sodium acetate in water and 83.3% 0.01 M acetic acid in water. The buffer contains 0.0009% (w/v) sodium azide.
-Phosphate buffer pH 7, 0.01 M: Solution of 0.01 M potassium di-hydrogenphosphate in water adjusted to pH 7 using 1 N sodium hydroxide. The buffer contains 0.0009% (w/v) sodium azide.
-Borate buffer pH 9, 0.01 M: Solution of 0.01 M boric acid in water and 0.01 M potassium chloride in water adjusted to pH 9 using 1 N sodium hydroxide. The buffer contains 0.0009% (w/v) sodium azide.

Details on test conditions:

TEST SYSTEM
- Type, material and volume of test flasks, other equipment used: sterile vessel
- Sterilisation method: buffer solutions were filter-sterilised through a 0.2 µm FP 30/0.2 CA-S filter (Wathman, Dassel, Germany) and transferred into a sterile vessel.
- Lighting:
* Tier 1: in the dark
* Tier 2: test at 20°C was performed twice due to possible combination of photolysis and hydrolysis. During the first study test samples were incubated under yellow light and during the second study in the dark.
- Measures taken to avoid photolytic effects: vessels placed in the dark
- Measures to exclude oxygen: nitrogen gas was purged through the solution for 5 minutes
- Details on test procedure for unstable compounds: no data
- Details of traps for volatile, if any: not applicable
- If no traps were used, is the test system closed/open: under vacuum
- Is there any indication of the test material adsorbing to the walls of the test apparatus? no

TEST MEDIUM
- Volume used/treatment: 6 mL
- Kind and purity of water: Milli-Q
- Preparation of test medium: The test item was spiked to the solutions at a target concentration of 0.200 mg/L using a spiking solution in acetonitrile.
- Renewal of test solution: not applicable
- Identity and concentration of co-solvent: not applicable

OTHER TEST CONDITIONS
- Adjustment of pH: no
- Dissolved oxygen: no data

Duration:

5 d

pH:

4

Temp.:

49.9 °C

Initial conc. measured:

>= 0.208 - <= 0.215 mg/L

Duration:

5 d

pH:

7

Temp.:

49.9 °C

Initial conc. measured:

>= 0.244 - <= 0.247 mg/L

Duration:

5 d

pH:

9

Temp.:

49.9 °C

Initial conc. measured:

0.25 mg/L

Duration:

651.55 h

pH:

4

Temp.:

19.9 °C

Initial conc. measured:

>= 0.202 - <= 0.213 mg/L

Duration:

721.03 h

pH:

4

Temp.:

49.7 °C

Initial conc. measured:

>= 0.183 - <= 0.184 mg/L

Duration:

162.8 h

pH:

4

Temp.:

59.9 °C

Initial conc. measured:

>= 0.181 - <= 0.184 mg/L

Duration:

745.17 h

pH:

7

Temp.:

19.9 °C

Initial conc. measured:

>= 0.204 - <= 0.206 mg/L

Duration:

722.98 h

pH:

7

Temp.:

49.7 °C

Initial conc. measured:

>= 0.165 - <= 0.169 mg/L

Duration:

218.02 h

pH:

7

Temp.:

59.9 °C

Initial conc. measured:

>= 0.172 - <= 0.175 mg/L

Duration:

649.1 h

pH:

9

Temp.:

19.9 °C

Initial conc. measured:

>= 0.186 - <= 0.19 mg/L

Duration:

577.23 h

pH:

9

Temp.:

49.7 °C

Initial conc. measured:

>= 0.173 - <= 0.174 mg/L

Duration:

215.57 h

pH:

9

Temp.:

59.9 °C

Initial conc. measured:

>= 0.172 - <= 0.182 mg/L

Number of replicates:

- Calibration solutions: duplicate
- Test samples: single injection

Positive controls:

no

Negative controls:

no

Statistical methods:

no data

Preliminary study:

- A degree of hydrolysis ≥ 10% was observed at pH 4, pH 7 and pH 9 after 5 days, a higher tier test was performed.
- The mean recoveries of the buffer solutions at t=0 fell within the acceptable range of 70-110% for non-labelled chemicals. It demonstrated that the analytical method was adequate to support the hydrolysis study on the test item.

Transformation products:

no

% Recovery:

106

pH:

4

Temp.:

50 °C

Duration:

5 d

Remarks on result:

other: mean recovery

% Recovery:

123

pH:

7

Temp.:

50 °C

Duration:

5 d

Remarks on result:

other: mean recovery

% Recovery:

125

pH:

9

Temp.:

50 °C

Duration:

5 d

Remarks on result:

other: mean recovery

% Recovery:

104

pH:

4

Temp.:

20 °C

Duration:

651.55 h

% Recovery:

92

pH:

4

Temp.:

50 °C

Duration:

721.03 h

% Recovery:

91

pH:

4

Temp.:

60 °C

Duration:

162.8 h

% Recovery:

102

pH:

7

Temp.:

20 °C

Duration:

745.17 h

% Recovery:

84

pH:

7

Temp.:

50 °C

Duration:

722.98 h

% Recovery:

87

pH:

7

Temp.:

60 °C

Duration:

218.02 h

% Recovery:

94

pH:

9

Temp.:

20 °C

Duration:

649.1 h

% Recovery:

87

pH:

9

Temp.:

50 °C

Duration:

577.23 h

% Recovery:

89

pH:

9

Temp.:

60 °C

Duration:

215.57 h

pH:

4

Temp.:

25 °C

Hydrolysis rate constant:

0.003 h-1

DT50:

9.2 d

Type:

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

Remarks on result:

other: under yellow light

Key result

pH:

7

Temp.:

25 °C

Hydrolysis rate constant:

0.001 h-1

DT50:

26 d

Type:

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

Remarks on result:

other: under yellow light

pH:

9

Temp.:

25 °C

Hydrolysis rate constant:

0.005 h-1

DT50:

5.9 d

Type:

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

Remarks on result:

other: under yellow light

pH:

4

Temp.:

25 °C

Hydrolysis rate constant:

0.011 h-1

DT50:

2.8 d

Type:

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

Remarks on result:

other:

Remarks:

in the dark

Key result

pH:

7

Temp.:

25 °C

Hydrolysis rate constant:

0.004 h-1

DT50:

7.2 d

Type:

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

Remarks on result:

other: in the dark

pH:

9

Temp.:

25 °C

Hydrolysis rate constant:

0.008 h-1

DT50:

3.4 d

Type:

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

Remarks on result:

other: in the dark

For testing of pseudo-first order kinetics the mean logarithms of the relative concentrations between 10% and 90% were plotted against time. The half-life times of the test item were determined according to the model for pseudo-first order reactions. All logarithms of the relative concentrations were correlated with time using linear regression analysis.

The rate constant (kobs) and half-life time of the test item at each temperature was obtained and the Arrhenius equation was used to determine the rate constant and half-life time.

Validity criteria fulfilled:

yes

Conclusions:

The preliminary test (Tier 1) and main study (Tier 2) were performed for the determination of the rate of hydrolysis of JNJ-42808415-AAA (T003422) at pH values normally found in the environment (pH 4-9). Test at 20°C was performed twice due to possible combination of photolysis and hydrolysis. During the first study test samples were incubated under yellow light and during the second study in the dark. The half-life times (days) for the test item in the dark at pH 4, 7 and 9 at 25°C were 2.8, 7.2 and 3.4 days respectively. The results of the test can be considered reliable without restrictions.

Description of key information

One study (Ciric, 2017) was performed according to OECD 111 and regarded as a key study (Klimisch score of 1). In the dark, half-life (DT50) times of 2.8, 7.2 and 3.4 days at pH 4, 7 and 9 at 25°C respectively was determined for T003422.

Under yellow light, half-life (DT50) times of 9.2, 26 and 5.9 days at pH 4, 7 and 9 at 25°C respectively was determined for T003422. Results of this study can be considered reliable without restriction.

Key value for chemical safety assessment

Half-life for hydrolysis:

7.2 d

at the temperature of:

25 °C