Reaction mass of [[(2-hydroxyethyl)imino]bis(methylene)]bisphosphonic acid and Phosphonic acid, P-[(tetrahydro-2-hydroxy-2-oxido-4H-1,4,2-oxazaphosphorin-4-yl)methyl]-

Endpoint summary

Additional information

There are no data on the toxicokinetics of 2-hydroxyethyliminodimethanephosphonic acid (HEBMP-H).

The following summary has therefore been prepared based on the physicochemical properties of HEBMP itself and using this data in algorithms that are the basis of many computer-based physiologically based pharmacokinetic or toxicokinetic (PBTK) prediction models. The main input variable for the majority of these algorithms is log K_owso by using this, and other where appropriate, known or predicted physicochemical properties of HEBMP a reasonable prediction or statement may be made about its potential absorption, distribution, metabolism and excretion (ADME) properties.

Relevant human exposure can occur via the oral, inhalation or dermal routes.

Absorption

Oral

When oral exposure takes place it can be assumed, except for the most extreme of insoluble substances, that uptake through intestinal walls into the blood occurs. Uptake from intestines can be assumed to be possible for all substances that have appreciable solubility in water or lipid. Other mechanisms by which substances can be absorbed in the gastrointestinal tract include the passage of small water-soluble molecules (molecular weight up to around 200) through aqueous pores or carriage of such molecules across membranes with the bulk passage of water (Renwick, 1993).

Although the molecular weight of HEBMP-H (approximately 250) is above the favourable range for absorption, due to its very high water solubility it is likely that absorption from the gastrointestinal tract would occur. In an oral acute study with the acid form (SafePharm, 2003) signs of toxicity were noted indicating that absorption of test substance-related material had occurred.

Dermal

The fat solubility and therefore potential dermal penetration of a substance can be estimated by using the water solubility and log K_ow values. Substances with log K_ow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high. Therefore, although the water solubility of HEBMP is very high, the log K_ow of -4 is significantly outside the favourable range so dermal absorption is unlikely to occur.

In an acute dermal study with the sodium salt of HEBMP (Harlan, 2012) there were no signs of systemic toxicity.

Inhalation

There is a Quantitative Structure-Property Relationship (QSPR) to estimate the blood:air partition coefficient for human subjects as published by Meulenberg and Vijverberg (2000). The resulting algorithm uses the dimensionless Henry coefficient and the octanol:air partition coefficient (K_oct:air) as independent variables. 

Using these values for HEBMP predicts an extremely high blood:air partition coefficient (approximately 8.6E+08:1), so should inhaled exposure occur, absorption across the respiratory tract epithelium is likely.

There are no inhaled toxicity studies to confirm evidence of absorption of the test material.

Distribution

For blood:tissue partitioning a QPPR algorithm has been developed by DeJongh et al. (1997) in which the distribution of compounds between blood and human body tissues as a function of water and lipid content of tissues and the n-octanol:water partition coefficient (K_ow) is described.

Using this for HEBMP-H predicts that should systemic exposure occur distribution would be minimal with tissue:blood partition coefficients of less than 1 for all tissues (zero for fat).

Table 5.1.1: Tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
HEBMP-H	-4.0	1E-04	0.6	0.7	0.0	0.7	0.8

 Sodium ions will enter the body's natural homeostatic processes.

Metabolism

There are no data regarding the metabolism of HEBMP-H. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation for HEBMP-H and its salts.

Excretion

A determinant of the extent of urinary excretion is the soluble fraction in blood. QPSRs as developed by DeJongh et al. (1997) using log K_ow as an input parameter, calculate the solubility in blood based on lipid fractions in the blood assuming that human blood contains 0.7% lipids.

 

Using this algorithm, the soluble fraction of HEBMP in blood is >99% suggesting it is likely to be effectively eliminated via the kidneys in urine and accumulation is very unlikely.

Renwick A. G. (1993) Data-derived safety factors for the evaluation of food additives and environmental contaminants.Fd. Addit. Contam.10: 275-305.

Meulenberg, C.J. and H.P. Vijverberg, Empirical relations predicting human and rat tissue:air partition coefficients of volatile organic compounds. Toxicol Appl Pharmacol, 2000. 165(3): p. 206-16.

DeJongh, J., H.J. Verhaar, and J.L. Hermens, A quantitative property-property relationship (QPPR) approach to estimate in vitro tissue-blood partition coefficients of organic chemicals in rats and humans. Arch Toxicol, 1997.72(1): p. 17-25