Dimethyl octadecylphosphonate

Endpoint summary

Additional information

In a GLP, guideline compliant Ames test, (Riach, CG. (2012) ), dimethyl octadecylphosphonate (also known as DMOP) was tested for mutagenic activity in Salmonella typhimurium strains TA 1535, TA 1537, TA 98 and TA 100 and in Escherichia coliWP2uvrA. DMOP was dissolved and diluted in ethanol. Two independent tests were conducted on agar plates in triplicate in the absence and presence of an Aroclor 1254-induced rat liver S9 preparation and the co-factors required for mixed function oxidase activity (S9 mix). The first test was conducted by the Direct Plate Incorporation Method, while the second test was conducted by the Pre-incubation Method. DMOP was dosed at concentrations ranging from 17 to 5000 μg per plate in both the absence and the presence of S9 mix. The highest concentration represents the maximum recommended by OECD Guideline 471. Concurrent positive controls demonstrated the sensitivity of the assay and the metabolising activity of the S9 mix.

No evidence of mutagenic activity was obtained with any strain in either test. DMOP was not toxic to the bacteria, however, it precipitated at the 2 highest concentrations of 1667 and 5000 μg per plate, in both tests, in both the absence and the presence of S9 mix.

In conclusion, DMOP was not mutagenic in strains ofSalmonella typhimuriumandEscherichia coliwhen dissolved and diluted in ethanol and tested in the absence and presence of metabolic activation at concentrations up to and above its limit of solubility in the test system.

 

In a GLP, in vitro mammalian cell gene mutation test, (Riach, CG. (2013) ), dimethyl octadecylphosphonate (also known as DMOP), was assayed for mutagenic potential in the mouse lymphoma L5178Y cell line. Tests were conducted both in the absence and in the presence of a metabolic activation S9 mix. The study was designed to be consistent with ICH Guidelines, OECD Guideline No. 476 and EC Directive 2000/32/EC B.17.

Preliminary cytotoxicity tests showed that DMOP was of a moderate to high order of toxicity, reducing cell growth over the range 3.3 to 33.3 μg/mL (4 h exposure period) and over the range 1.67 to 50 μg/mL (24 h exposure period). Four independent mutation assays were conducted and positive control cultures and vehicle control cultures were included. Duplicate cultures were carried through the experiments for each treatment point with vehicle control cultures tested in quadruplicate.

No biologically relevant increase in mutant fraction was obtained in either the absence or the presence of S9 mix although it was noted that small increases considered to be of no biological relevance were obtained in the DMOP treatment groups in the presence of S9 mix.

Results were obtained at a definitive level of toxicity in both the absence and the presence of S9 mix. In conclusion, DMOP was not mutagenic in mouse lymphoma L5178Y cells, in either the absence or the presence of S9 mix when tested in ethanol at concentrations extending into the toxic range.

 

In a GLP, in vitro mammalian cell chromosomal aberration test, (Murie, E. (2013) ), dimethyl octadecylphosphonate (also known as DMOP), was assayed for clastogenic potential in Chinese hamster ovary cell cultures (in duplicate) according to the OECD 473 guideline. This study was conducted incorporating 2 independent tests. Ethanol was the vehicle and cyclophosphamide and methyl methanesulphonate were the positive controls used in both tests. Both tests were conducted in the presence and absence of S9 metabolic activation mix.  

Cultures, established 20-24 h before testing, were treated for 6 h in the presence and 6 h or 22 h in the absence of S9 mix. Cultures were harvested at 24 h or 48 h post treatment. DMOP was toxic to Chinese hamster ovary cells in vitro in both the presence and absence of S9 mix. It was tested up to the maximum permitted concentration of 5000 µg/mL in the presence of S9 mix and up to 80 µg/mL in the absence of S9 mix. Toxicity was noted over the range 39-5000 µg/mL in the presence of S9 mix and over the range 10-80 µg/mL in the absence of S9 mix depending on the 24 or 48 harvest times. There was no evidence that DMOP induced structural chromosomal aberrations in either the presence or absence of S9 mix.

Justification for selection of genetic toxicity endpoint
Weight of evidence conclusion based on negative outcomes from 1 in-vitro study in bacterial cells and 2 in vitro studies in mammalian cells.

Short description of key information:
One in-vitro study in bacterial cells and 2 in vitro studies in mammalian cells are available. All studies were negative with respect to genetic toxicity.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

No classification:

All in vitro tests are negative