4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin

Water solubility

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

water solubility

Data waiving:

study technically not feasible

Justification for data waiving:

other:

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
Solubility and analytical investigations were performed in a scientifically reasonable and well documented manner in order to assess the possibility / feasibility to perform both a water solubility and hydrolysis study according to OECD 105 resp. 111.
NMR-spectroscopy was used to identify the structure of CAS 73912-21-7. 31P NMR spectrum using deuterated toluene shows one structure for 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin. Spectra done with other solvents indicate decay of 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin into raw material and phosphonic acid in the presence of water.
Tests were done on 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin to clarify if fast hydrolysis at pH 4 takes place. Qualitative tests showed, that no suitable solvent system for monitoring in-situ hydrolysis of 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin in water was found.
The water solubility of 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin was analyzed according to OECD guideline 105. In the first test 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin and raw material could be detected after shaking the pastilles with water for three days. Due to increasing values the test had to be repeated.
The replicate test was done with the pastilles crushed into fine powder and shaking the samples in the dark for 7 days. First analysis was done on day 3, detecting the raw material, no 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin could be detected. From day 4 to 7 the chromatograms show only peaks for the internal standard. The pH-values were stable from day 5 to day 7. In addition the insoluble residue in the flasks was analyzed on day 3.
The results show, that 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin degrades in water over time into raw material. Both substances are insoluble in water, the besides that formed phosphonic acid is soluble in water and lowers the pH-value of the solution.
The feasibility of a hydrolysis study with 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin was assessed by a CRO. The solubility of the test item in water was estimated to be 1.171*10-8 mg/L at 25 °C (EPI Suite 4.11). The results of the experiments indicated that reproducible results could only be obtained in the absence of water, either due to the very low water solubility or due to the stability of the test item in water. A study to investigate the hydrolytic properties of 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin will not be performed, because no analytical method with appropriate sensitivity is available or could be developed.
The NMR-results indicate that although insoluble in water 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin degrades in the presence of water.
The water solubility experiments show that the composition of the solid residue changes over time: The amount of 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin is reduced from 89.3% (day 0) to 38.5% (day 3). 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin decomposes into the raw material which increases in the insoluble residue from 7.3% (day 0) to 38.5% (day 3). That again indicates decomposition of 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin in the presence of water though insoluble in water. It was not possible to obtain reproducible results for the water solubility.
The independent institute came to the same conclusion stating “the results of the experiments indicated that reproducible analytical results could only be obtained in the absence of water.” This is in support of results at another CRO stating that “no suitable solvent system for monitoring the hydrolysis of 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin was found.”
In consequence, both water solubility and hydrolysis study according to OECD 105 resp. 111 cannot be performed, and testing can be omitted as it is technically not feasible.

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Reference 2

Endpoint:

water solubility

Type of information:

other: Expert assessment based on various experimental results

Adequacy of study:

key study

Study period:

until 2017-05-29

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Expert statement supported well-documented experimental results assessed as Klimisch 1 or 2

Reason / purpose for cross-reference:

data waiving: supporting information

Remarks:

Present information supports data waiving

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

other: If not stated otherwise all reported tests were performed according to internal standard operation procedures and methods, describing the operation for the employed instruments and analytical techniques.

Deviations:

no

GLP compliance:

not specified

Other quality assurance:

other: All internal investigations reported in this summary were performed in the Quality Management Laboratory of the owner company. Original reports and raw data are stored in our archives.

Type of method:

other: Expert assessment based on various experimental results

Key result

Remarks on result:

other: not determinable; test item is insoluble.

Conclusions:

Solubility and analytical investigations were performed in a scientifically reasonable and well documented manner in order to assess the possibility / feasibility to perform both a water solubility and hydrolysis study according to OECD 105 resp. 111 as stipulated under REACH for registrations > 1 resp. 10 tpa.
NMR spectra done with other solvents indicate decay of the test item into raw material and phosphonic acid in the presence of water, no suitable solvent system for monitoring in-situ hydrolysis in water was found. Water solubility determinations show, that 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin degrades in water over time into raw material. Both substances are insoluble in water, the besides that formed phosphonic acid is soluble in water and lowers the pH-value of the solution.
The solubility of the test item in water was estimated to be 1.171*10-8 mg/L at 25 °C (EPI Suite 4.11). A study to investigate the hydrolytic properties of 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin can not be performed, because no analytical method with appropriate sensitivity is available or could be developed.
The NMR-results indicate that although insoluble in water 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin degrades in the presence of water.
In consequence, both water solubility and hydrolysis study according to OECD 105 resp. 111 cannot be performed, and testing can be omitted as it is technically not feasible.

Executive summary:

Solubility and analytical investigations were performed in a scientifically reasonable and well documented manner in order to assess the possibility / feasibility to perform both a water solubility and hydrolysis study according to OECD 105 resp. 111.

NMR-spectroscopy was used to identify the structure of CAS 73912-21-7. ³¹P‑NMR spectrum using deuterated toluene shows one structure for 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin. Spectra done with other solvents indicate decay of 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin into raw material and phosphonic acid in the presence of water.

Tests were done on 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin to clarify if fast hydrolysis at pH 4 takes place. Qualitative tests showed, that no suitable solvent system for monitoring in-situ hydrolysis of 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin in water was found.

The water solubility of 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin was analyzed according to OECD guideline 105. In the first test 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin and raw material could be detected after shaking the pastilles with water for three days. Due to increasing values the test had to be repeated.

The replicate test was done with the pastilles crushed into fine powder and shaking the samples in the dark for 7 days. First analysis was done on day 3, detecting the raw material, no 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin could be detected. From day 4 to 7 the chromatograms show only peaks for the internal standard. The pH-values were stable from day 5 to day 7. In addition the insoluble residue in the flasks was analyzed on day 3.

The results show, that 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin degrades in water over time into raw material. Both substances are insoluble in water, the besides that formed phosphonic acid is soluble in water and lowers the pH-value of the solution.

The feasibility of a hydrolysis study with 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin was assessed by a CRO. The solubility of the test item in water was estimated to be 1.171*10^-8 mg/L at 25 °C (EPI Suite 4.11). The results of the experiments indicated that reproducible results could only be obtained in the absence of water, either due to the very low water solubility or due to the stability of the test item in water. A study to investigate the hydrolytic properties of 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin will not be performed, because no analytical method with appropriate sensitivity is available or could be developed.

The NMR-results indicate that although insoluble in water 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin degrades in the presence of water.

The water solubility experiments show that the composition of the solid residue changes over time: The amount of 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin is reduced from 89.3% (day 0) to 38.5% (day 3). 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin decomposes into the raw material which increases in the insoluble residue from 7.3% (day 0) to 38.5% (day 3). That again indicates decomposition of 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin in the presence of water though insoluble in water. It was not possible to obtain reproducible results for the water solubility.

The independent institute came to the same conclusion stating “the results of the experiments indicated that reproducible analytical results could only be obtained in the absence of water.” This is in support of results at another CRO stating that “no suitable solvent system for monitoring the hydrolysis of 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin was found.”

In consequence, both water solubility and hydrolysis study according to OECD 105 resp. 111 cannot be performed, and testing can be omitted as it is technically not feasible.

Reference 3

Endpoint:

water solubility

Type of information:

experimental study

Adequacy of study:

key study

Study period:

until 2015-06-30

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Remarks:

acceptable restrictions

Reason / purpose for cross-reference:

data waiving: supporting information

Remarks:

Present information supports data waiving

Qualifier:

according to guideline

Guideline:

OECD Guideline 105 (Water Solubility)

Deviations:

not specified

GLP compliance:

no

Type of method:

flask method

Key result

Incubation duration:

24 h

pH:

5.2

Remarks on result:

other: not determinable; no substance was detected.

Key result

Incubation duration:

48 h

pH:

6

Remarks on result:

other: not determinable; only 31 µg/l CAS 4066-02-8 was formed, but not the registered substance itself.

Water solubility:

31 µg/L

Incubation duration:

48 h

pH:

6

Remarks on result:

other: identity of the measured compound: CAS 4066-02-8

Key result

Water solubility:

106 µg/L

Incubation duration:

72 h

pH:

4

Remarks on result:

other: in addition, 275µg/l CAS 4066-02-8 was detected

Water solubility:

381 µg/L

Incubation duration:

72 h

pH:

4

Remarks on result:

other: present peak corresponds to 106 µg/l of CAS 73912-21-7 and 275 µg/l CAS 4066-02-8

Conclusions:

Water solubility was determined in-house acc. OECD TG 105 (shake flask method) and is sufficiently documented, hence, the results can considered to be reliable. After 24h, the pH value decreased to 5.2, no peak resulting from the substance was detected. After 48h, pH value was found to be 6.0, and not the registered substance itself, but CAS 4066-02-8 was detected with a content of 31µg/l. After 72h, 106 µg/l of CAS 73912-21-7 and 275 µg/l CAS 4066-02-8 were detected at a pH value of 4.0.
CAS 4066-02-8 is related to CAS 73912-21-7, it is basically the same molecule without the phosphor bridge between the two oxygen atoms. In combination with the time-dependent decrease of the pH value, it can be concluded that minor amount of CAS 73912-21-7 are solved in water and under cleavage of PO3(3-) CAS 4066-02-8 is formed. However, it can be also concluded that CAS 73912-21-7 is practically insoluble in water.

Executive summary:

Water solubility is determined as set out in OECD TG 105, shake flask method. 2 g of the test item was shaken in 3 separate 500 ml Erlenmeyer flasks with 250 ml HPLC water (18.2 MOhm) for 24, 48, and 72 h at room temperature (20-23°C). The turbid aqueous phase was filtered via a folded filter and its pH value determined.

After 24h, the pH value decreased to 5.2, no peak resulting from the substance was detected. After 48h, pH value was found to be 6.0, and not the registered substance itself, but CAS 4066-02-8 was detected with a content of 31µg/l. After 72h, 106 µg/l of CAS 73912-21-7 and 275 µg/l CAS 4066-02-8 were detected at a pH value of 4.0.

It can be concluded that CAS 73912-21-7 is practically insoluble in water, and that CAS 4066-02-8 is formed.

Description of key information

NMR spectra done with other solvents indicate decay of the test item into raw material and phosphonic acid in the presence of water, no suitable solvent system for monitoring in-situ hydrolysis in water was found. Water solubility determinations show, that 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin degrades in water over time into raw material. Both substances are insoluble in water, besides that formed phosphonic acid is soluble in water and lowers the pH-value of the solution.

The solubility of the test item in water was estimated to be 1.171*10^-8 mg/L at 25 °C (EPI Suite 4.11). A study to investigate the hydrolytic properties of 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin can not be performed, because no analytical method with appropriate sensitivity is available or could be developed.

The NMR-results indicate that although insoluble in water 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin degrades in the presence of water.

In consequence, both water solubility and hydrolysis study according to OECD 105 resp. 111 cannot be performed, and testing can be omitted as it is technically not feasible.

Key value for chemical safety assessment

Water solubility:

0 µg/L

at the temperature of:

25 °C

Additional information

Substance is insoluble