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

Short-term toxicity to aquatic invertebrates

Administrative data

Endpoint:

short-term toxicity to aquatic invertebrates

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 highly insoluble in water, hence indicating that aquatic toxicity is unlikely to occur

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
According to REACH Annex VII column 1, 9.1.1. Short-term toxicity testing on invertebrates (preferred species Daphnia) The registrant may consider long-term toxicity testing instead of short-term. According to column 2, 9.1.1. The study does not need to be conducted if:
— there are mitigating factors indicating that aquatic toxicity is unlikely to occur, for instance if the substance is highly insoluble in water or the substance is unlikely to cross biological membranes, or
— a long-term aquatic toxicity study on invertebrates is available, or
— adequate information for environmental classification and labelling is available.
The long-term aquatic toxicity study on Daphnia (Annex IX, section 9.1.5) shall be considered if the substance is poorly water soluble.

In general, there is no legal limit value available defining a substance as poorly water soluble or insoluble under REACH. However, in ECHA’s Guidance document Chapter R.7b: Endpoint specific guidance Version 3.0 – February 2016, it is stated: „poorly water soluble substances (e.g. water solubility below 1 mg/L or below the detection limit of the analytical method of the test substance)“. Further, poorly soluble substances are defined by OECD (2000 OECD SERIES ON TESTING AND ASSESSMENT, Number 23, GUIDANCE DOCUMENT ON AQUATIC TOXICITY TESTING OF DIFFICULT SUBSTANCES AND MIXTURES, ENV/JM/MONO(2000)6) as substances with a limit of solubility <100 mg/l although technical problems are more likely to occur at <1mg/l as defined in TGD (1996). Very low water solubility (i.e. in the low μg/l range) could be used as a reason to significantly modify a standard test or to test non-pelagic organisms preferentially.
ECHA’s Guidance document Chapter R.7c: Endpoint specific guidance Version 3.0 – June 2017 further says: „As indicated in the OECD TG 305, for strongly hydrophobic substances (log Kow > 5 and a water solubility below ~ 0.01-0.1 mg/L), testing via aqueous exposure may become increasingly difficult. However, an aqueous exposure test is preferred for substances that have a high log Kow but still appreciable water solubility with respect to the sensitivity of available analytical techniques, and for which the maintenance of the aqueous concentration as well as the analysis of these concentrations do not pose any constraints.

The registrant did conduct or had conducted various studies ahead, as a part of a tiered approach, to establish suitable conditions including analytics for water solubility and hydrolysis testing. Details can be found in the respective chapters, summarizing however it can be stated the following:
NMR spectra done with other solvents than water 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.
In consequence, both water solubility and hydrolysis study according to OECD 105 resp. 111 cannot be performed, and testing is technically not feasible.

Based on the available information it can be stated that, as outlined in the first waiving possibility under REACH, the substance is highly insoluble in water, and hence, aquatic toxicity is unlikely to occur. The latter conclusion is supported by available studies conducted prior to REACH implementation, i.e. each a study according to EU method C.1 and EU method C.11. In those studies, no effects were noted in concentration of 1 mg/l (C.1) resp. 10 g/l (C.11), which are way above the possible water solubility of the registered substance. Hence, a study of the acute toxicity of the registered substance against daphnids does not need to be conducted.

With a estimated water solubility of 1.171*10-8 mg/L the substance does not only need to be regarded as poorly soluble but practically insoluble in water. Hence, long-term testing does also not need to be conducted, as very low water solubility can be assumed if the substance is soluble only in the low μg/l range, and the actual water solubility is way below. Further, the registrant demonstrated that the analysis of concentrations in water poses constraints, the sensitivity of available analytical techniques is not sufficient to analyse concentrations in the estimated water solubility range of 1E-8 mg/l.

In consequence, testing can be omitted.

Cross-reference

Reason / purpose for cross-reference:

read-across: supporting information

Reference

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