Phosphoric acid, mono- and di-C16-18-alkyl esters

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Assessment based upon available information.

Adequacy of study:

key study

Study period:

June 2019

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Information selected for the toxicokinetic assessment is primarily study data. Studies were conducted inaccordance with recognised testing guidelines.

Data source

Reference

Reference Type:

other: Assessment

Title:

Unnamed

Year:

2019

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Octadecyl dihydrogen phosphate

EC Number:

220-983-1

EC Name:

Octadecyl dihydrogen phosphate

Cas Number:

2958-09-0

Molecular formula:

C18H39O4P

IUPAC Name:

octadecyl dihydrogen phosphate

Constituent 2

Reference substance name:

Hexadecyl dihydrogen phosphate

EC Number:

222-581-1

EC Name:

Hexadecyl dihydrogen phosphate

Cas Number:

3539-43-3

Molecular formula:

C16H35O4P

IUPAC Name:

hexadecyl dihydrogen phosphate

Constituent 3

Reference substance name:

Dioctadecyl hydrogen phosphate

EC Number:

221-237-8

EC Name:

Dioctadecyl hydrogen phosphate

Cas Number:

3037-89-6

Molecular formula:

C36H75O4P

IUPAC Name:

dioctadecyl hydrogen phosphate

Constituent 4

Reference substance name:

Dihexadecyl hydrogen phosphate

EC Number:

218-594-7

EC Name:

Dihexadecyl hydrogen phosphate

Cas Number:

2197-63-9

Molecular formula:

C32H67O4P

IUPAC Name:

dihexadecyl hydrogen phosphate

Constituent 5

Reference substance name:

hexadecyl octadecyl hydrogen phosphate

Cas Number:

93803-11-3

Molecular formula:

C34H71O4P

IUPAC Name:

hexadecyl octadecyl hydrogen phosphate

impurity 1

Reference substance name:

Unidentified impurities, likely the C16 and C18, and mixed C16/C18 trialkyl phosphates based 31P NMR chemical shift.

Molecular formula:

N/A

IUPAC Name:

Unidentified impurities, likely the C16 and C18, and mixed C16/C18 trialkyl phosphates based 31P NMR chemical shift.

Test material form:

solid

Details on test material:

CAS Number 39471-52-8

Results and discussion

Any other information on results incl. tables

The test material, is a multi-constituent substance with five constituents in the molecular weight range of 322 to 602 daltons.  Only one of the five constituentsis present at less than 10%.

 

The substance is a waxy solid at room temperature with a melting point range of 51 to 69 deg.C at 101.3 kPa and a vapor pressure of 0.004 Pa at 25 deg. C. The substance is not expected to be respirable.

 

The substance is highly insoluble in water,with a measured water solubility of 0.162 mg/L. The partition coefficients (Log Pow) are less than 0.3 to 2.31.

 

These data indicate that the substance is not bioavailable via the oral route based on Lipinski’s Rule (Oasis structure-activity relationship (SAR) analysis). Additionally, the substance did not result in any systemic effects up to the limit doses tested in oral toxicology studies in rats, including up to 2000 mg/kg in the acute oral toxicity study, and up to1000 mg/kg/day in the14-day repeated dose oral range-finding toxicity study. In the 90-day repeated dose oral toxicity studyandtheprenatal developmental toxicitystudyin rats,systemic toxicity was not established due to the inherent physical properties of the substance. The arachis oil dose formulation of the substance, particularly the 1000 mg/kg/day dose formulation, became a white wax-like substance at room temperature and had to be warmed to approximately 46 deg.C to keep it ina liquid state prior to administration to rats. There is evidence of resolidification in the stomach, which probably impacted normalgastrointestinal (GI)function and led to a decline in physical condition for some rats; thus several mortalities at 1000 mg/kg/daywere considered to result from the intrinsic physical properties of the unabsorbed substance formulation rather than any systemic effect. SAR analysis also shows that the substance may be hydrolyzed releasing fatty alcohol and phosphoric acid. Some alkyl phosphates are used in cosmetics, and a toxicokinetic study of phosphoric acid, 2-ethylhexyl ester in rats has been reported.[1] In the study, a single oral dose of 200 mg/kg phosphoric acid, 2-ethylhexyl ester in corn oil to F344 rats (5/sex) was completely hydrolyzed to phosphate and 2-ethyl-hexanol. The ester was efficiently absorbed, metabolized, and excreted quantitatively by the body, and there was no indication of accumulation.

 

The physical/chemical properties of the substance also indicate that the substance is not expected to be absorbed via the dermal route. The hydrolytic metabolites of the substance, fatty alcohol, may be absorbed through skin, however.

 

The ready biodegradability test of the substance showed that it was considered not readily biodegradable. The analysis of the test preparations showed measured test concentrations of less than the limit of quantification (LOQ, 0.062 mg/L) in the acute toxicity test in Daphnia magna. Based on the available information, there is no indication of a bioaccumulation potential.

 

In conclusion, based upon the available data, bioavailability of the substance, the test material is expected to be limited, and the substance has low systemic toxicity.

[1]CIR, Safety Assemment of Alkyl Phosphates as Used in Cosmetics. Final report, September 29, 2014, Cosmetic Ingredient Review, Washington, DC.

Applicant's summary and conclusion

Conclusions:

In conclusion, based upon the available data, bioavailability of the substance, the test material is expected to be limited, and the substance has low systemic toxicity.