Triphenyl phosphite

Hydrolysis

Administrative data

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 111 (Hydrolysis as a Function of pH)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Triphenyl phosphite

EC Number:

202-908-4

EC Name:

Triphenyl phosphite

Cas Number:

101-02-0

Molecular formula:

C18H15O3P

IUPAC Name:

triphenyl phosphite

Test material form:

liquid

Specific details on test material used for the study:

Batch Number: U-16-00247

Radiolabelling:

no

Study design

Analytical monitoring:

yes

Buffers:

pH 4 buffer solution:
The 0.1 M acetic acid was prepared by diluting 5.8 mL of acetic acid (17.4 M) in a 1.0 L volumetric flask which was brought to the 1.0 L mark with HPLC grade bottled water. The 0.1 M sodium acetate was prepared by dissolving 4.1019 g sodium acetate with HPLC grade water brought to the 500 mL mark in a 500 mL volumetric flask. The 1.0 M ammonium acetate was prepared by dissolving 19.2706 g ammonium acetate with HPLC grade water brought to the 250 mL mark in a 250 mL volumetric flask. Acetate buffer (0.01M acetate; EAG ID: 10 mM acetate buffer-071117) was prepared by mixing 76 mL of 0.1 M acetic acid, 700 mL HPLC grade water, 4.0 mL of 0.1 M sodium acetate, and 1.6 mL of 1.0 M ammonium acetate. The buffer solution was mixed via stirring with a stir bar on a stir plate. The pH of the resulting solution was recorded at 4.01 and no pH adjustment was made. A volume of 18.4 mL HPLC grade water was added to the buffer solution to bring up to a total volume of 800 mL. The presence of 2 mM final concentration of ammonium acetate in the buffer was designed to help reduce possible non-specific binding of silanol groups of silica gel with TPP and potential degradants during hydrolysis. All the solutions mentioned above were stored in a refrigerator when not used.

pH 7 buffer solution:
The 0.01 M MOPS was prepared by dissolving 4.1854 g MOPS with HPLC grade water brought to the 2.0 L mark in a 2.0 L volumetric flask. Two batches of MOPS buffer were prepared for adjusting pH at room temperature (approximately 20 °C) or at 12 °C, respectively to account for possible small changes of buffer pH due to temperature difference [5]. For MOPS buffer used for TPP hydrolysis at 20 °C (0.01 M; EAG ID: 10 mM MOPS buffer-080417), 1000 mL of 0.01 M MOPS was mixed with 2.0 mL of 1.0 M ammonium acetate. The pH of the buffer solution was adjusted to 7.01 with approximately 0.7 mL of 6 N NaOH made in HPLC grade water. For MOPS buffer used for TPP hydrolysis at 12 °C (0.01 M, EAG ID: 10 mM MOPS buffer-082217), 0.01 M MOPS and 1.0 M ammonium acetate solutions were equilibrated inside an incubator set at 12 ± 0.5 ºC for approximately 6 hours. Then 900 mL of 0.01 M MOPS was mixed with 1.8 mL of 1.0 M ammonium acetate. The pH of the buffer solution was adjusted to 6.99 with approximately 0.5 mL of 6 N NaOH made in HPLC grade water. In addition to 2 mM final concentration of ammonium acetate in the buffer, the nitrogen atoms of the MOPS could also help block possible non-specific binding of silanol groups of silica gel with TPP and potential degradants during hydrolysis. All the solutions mentioned above were stored in a refrigerator when not used, except the MOPS buffer solution made at 12 °C, which was stored in an incubator set at 12 ± 0.5 ºC overnight before being used the next day.

pH 9 buffer solution:
The 0.01 M TAPS was prepared by dissolving 2.4339 g TAPS with HPLC grade water brought to the 1.0 L mark in a 1.0 L volumetric flask. 800 mL of 0.01 M TAPS was mixed with 1.6 mL of 1.0 M ammonium acetate. The pH of the buffer solution (ID: 0.01 M TAPS buffer-073117) was adjusted to 9.00 with approximately 0.98 mL of 6 N NaOH made in HPLC grade water. In addition to 2 mM final concentration of ammonium acetate in the buffer, the nitrogen atoms of the TAPS molecules could also help block possible non-specific binding of silanol groups of silica gel with TPP and potential degradants during hydrolysis. All the solutions mentioned above were stored in a refrigerator when not used .

Details on test conditions:

Test Vessels
The test vessels used for the hydrolysis testing were glass vials with approximately 24 mL volume. Prior to testing, approximately 0.15 g silica gel was weighed and transferred to each of the vials, which were placed inside an oven set at approximately 105 °C to dry the gel and sterilize the vessels for approximately 2 hours. The aluminum lined caps for the test vessels were UV light-sterilized for approximately 2 hours inside a clean bench with the liners facing up. The sterilized caps were wrapped with UV-sterilized aluminum foil and stored inside the clean bench prior to be used. Sterile desiccators were prepared by transferring approximately 100 g Drierite® to each of the 500 mL amber jars. The top of the Drierite® in each jar was covered with two layers of paper towel and were incubated inside the oven set at 105 °C for 2 hours. The lids for the jars were UV-sterilized for approximately 2 hours. The sterilized test vessels containing dried silica gel were taken out of the oven and immediately placed inside the sterilized desiccators and sealed with the sterilized lids for storage at room temperature prior to dosing of TPP.

Temperature Control
Temperatures were controlled by placing the test vessels on a rotator located inside the incubators set to maintain temperatures of 20 ± 0.5 ºC and 12 ± 0.5 ºC.

Test Monitoring
The pH values of the test solutions were measured at test initiation and termination for each pH test condition. The pH was determined using an Orion Star A111 or A2111 pH benchtop meter with an accuracy of ± 0.01 pH unit.

The temperatures of the incubators were monitored continuously with a VWR or Fisher Scientific traceable minimum/maximum thermometer and recorded each workday during the testing period.

Negative controls:

yes

Remarks:

TPP added to silica gel and incubated in anhydrous ACN.

Results and discussion

Preliminary study:

Multiple preliminary studies were conducted to determine the best approach for conducting the definitive study. See attached report for a full description of the preliminary testing.

Test performance:

See full report.

Transformation products:

yes

Identity of transformation products

No.:

#1

Reference

Reference substance name:

Unnamed

IUPAC name:

phenol

Inventory number:

InventoryMultipleMappingImpl [inventoryEntryValue=EC 203-632-7]

CAS number:

108-95-2

Identity:

Phenol

Molecular formula:

C6H6O

Molecular weight:

94.111

SMILES notation:

Oc1ccccc1

InChl:

InChI=1/C6H6O/c7-6-4-2-1-3-5-6/h1-5,7H

Details on hydrolysis and appearance of transformation product(s):

See full report.

Total recovery of test substance (in %)

Total recovery of test substance (in %) 1

% Recovery:

43.4

pH:

4.09

Temp.:

20 °C

Duration:

120 h

Total recovery of test substance (in %) 2

% Recovery:

78

pH:

7.05

Temp.:

20 °C

Duration:

53 h

Total recovery of test substance (in %) 3

% Recovery:

78

pH:

7.03

Temp.:

12 °C

Duration:

77 h

Total recovery of test substance (in %) 4

% Recovery:

84.1

pH:

8.99

Temp.:

20 °C

Duration:

27 h

Dissipation DT50 of parent compound

Dissipation DT50 of parent compound 1

Key result

pH:

4.09

Temp.:

20 °C

Hydrolysis rate constant:

0.032 h-1

DT50:

21.9 h

Type:

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

Dissipation DT50 of parent compound 2

Key result

pH:

7.03

Temp.:

12 °C

Hydrolysis rate constant:

0.047 h-1

DT50:

14.7 h

Type:

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

Dissipation DT50 of parent compound 3

Key result

pH:

7.05

Temp.:

20 °C

Hydrolysis rate constant:

0.106 h-1

DT50:

6.5 h

Type:

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

Dissipation DT50 of parent compound 4

Key result

pH:

8.99

Temp.:

20 °C

Hydrolysis rate constant:

1.605 h-1

DT50:

0.43 h

Type:

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

Details on results:

The study results indicate that TPP can be rapidly hydrolysed to phenol under different pH and temperature conditions if the test substance is available for hydrolytic reactions. There was no hydrolysis of TPP in anhydrous ACN indicating that the negative control was valid.

Applicant's summary and conclusion

Conclusions:

Triphenyl phosphite (TPP) was shown to hydrolyse to form phenol in sterile buffer solutions containing silica gel to facilitate dispersion of the test substance. Under acidic pH 4.09 at 20 ºC, TPP was partially hydrolysed with a maximum phenol yield of 43.4 mol%. In contrast, a maximum phenol yield of 78.0 mol% was observed under neutral pH 7.05 at 20 ºC and under pH 7.03 at 12 ºC. A maximum phenol yield of 84.1 mol% was observed under alkaline pH 8.99 at 20 ºC.

The rate constants of TPP hydrolysis to form phenol was pH dependent, with the highest rate of 1.6045 hour-1 occurring at pH 8.99 and lowest rate of 0.0316 hour-1 occurring at pH 4.09. The rate constant for the treatment pH 7.05 at 20 ºC was estimated to be 0.1065 hour-1. At 20 °C, the estimated DT50 of TPP in sterile buffer solutions was 21.9, 6.5, and 0.43 hours, respectively for pH 4.09, 7.05, and 8.99. At 12 °C, the estimated DT50 of TPP in sterile buffer solution for pH 7.03 was 14.7 hours, which is about 2-fold longer than that at 20 ºC. Virtually no TPP was hydrolysed to form phenol in silica gel and anhydrous ACN over 168 hours of incubation at 20 ºC.

The study results indicate that TPP can be rapidly hydrolysed to phenol under different pH and temperature conditions if the test substance is available for hydrolytic reactions.

Executive summary:

The study was performed on triphenyl phosphite (TPP) based on procedures in the OECD Guideline for the Testing of Chemicals, 111, Hydrolysis as a Function of pH.   The study was conducted to evaluate the rate of hydrolysis of the test substance in aqueous media in the pH range of 4 to 9 at 20 °C and at 12 °C for pH 7.  The experimental conditions were established based on previous non-GLP range-finding experiments.

TPP was shown to hydrolyse to form phenol in sterile buffer solutions containing silica gel to facilitate dispersion of the test substance.   Under acidic pH 4.09 at 20 ºC, TPP was partially hydrolysed with a maximum phenol yield of 43.4 mol%.  In contrast, a maximum phenol yield of 78.0 mol% was observed under neutral pH 7.05 at 20 ºC and under pH 7.03 at 12 ºC.  A maximum phenol yield of 84.1 mol% was observed under alkaline pH 8.99 at 20 ºC.   In none of the studies was there any evidence of other intermediates (i.e. monophenyl or diphenyl phosphite).

The rate constants of TPP hydrolysis to form phenol was pH dependent, with the highest rate of 1.6045 hour-1 occurring at pH 8.99 and lowest rate of 0.0316 hour-1 occurring at pH 4.09.  The rate constant for the treatment pH 7.05 at 20 ºC was estimated to be 0.1065 hour-1.   At 20 °C, the estimated DT50 of TPP in sterile buffer solutions was 21.9, 6.5, and 0.43 hours, respectively for pH 4.09, 7.05, and 8.99.   At 12 °C, the estimated DT50 of TPP in sterile buffer solution for pH 7.03 was 14.7 hours, which is about 2-fold longer than that at 20 ºC.  Virtually no TPP in silica gel was hydrolysed to form phenol in anhydrous ACN over 168 hours of incubation at 20 ºC.  

The study results indicate that TPP can be rapidly hydrolysed to phenol under different pH and temperature conditions if the test substance is available for hydrolytic reactions.