Barium bis(dihydrogenorthophosphate)

Endpoint summary

Description of key information

In the absence of specific data on the ADME of barium bis (dihydrogenorthophosphate), its physicochemical properties and relevant toxicity data (where available) were assessed for insights into likely ADME characteristics. Since barium bis(dihydrogenorthophosphate) will dissociate to Ba²⁺ ionsand the phosphate group also toxicokinetic information on other barium compounds were taken into account for the toxicokinetic assessment. Barium and thus barium bis (dihydrogenorthophosphate) is considered to be absorbed via oral and inhalation route. Barium bis (dihydrogenorthophosphate) is a solid metal compound and therefore considered to be badly absorbed via dermal route. Barium is described to be distributed mainly to the bones but also to soft tissues like heart, eye, kidney, and skeletal muscle. Barium is not metabolized in the body, but it may be transported or incorporated into complexes or tissues. The elimination of barium in both humans and animals occurs principally in the faeces rather than in the urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no studies available in which the toxicokinetic behaviour of barium bis(dihydrogenorthophosphate) (CAS 13466-20-1) has been investigated.

Therefore, in accordance with Annex VIII, Column 1, Section 8.8.1, of Regulation (EC) No 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014), assessment of the toxicokinetic behaviour of barium bis(dihydrogenorthophosphate) is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the physico chemical and toxicological properties according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014).

Barium bis(dihydrogenorthophosphate) is a solid at 20°C with a molecular weight of 331.3 g/mol and a water solubility of 27790 mg/L at 20°C. Since barium bis(dihydrogenorthophosphate) will dissociate to Ba²⁺ ions and the phosphate group also toxicokinetic information on other barium compounds were taken into account for the toxicokinetic assessment.

ABSORPTION:

Oral:

Reported absorption of barium in animal studies ranges from less than 1% to greater than 80%. Taylor et al. (1962) reported gastrointestinal absorption for a single gavage dose of 133BaCl2 in older (6 - 70 weeks of age) nonfasted rats to be 7% - 8%, compared to 20% in older fasted animals, and 63% - 84% in younger (14 - 22 days) nonfasted rats. These data suggest that both age and feeding status affect the absorption of barium.

McCauley and Washington (1983) and Stoewsand et al. (1988) compared absorption efficiencies of several barium compounds.¹³¹Ba-labeled barium sulfate and barium chloride were absorbed at “nearly equivalent rates” (based on blood and tissue levels) in rats following single gavage doses of the compounds each equaling 10 mg barium (McCauley and Washington, 1983). Similar concentrations of barium were found in the bones of rats fed diets with equivalent doses of barium chloride or barium from Brazil nuts. McCauley and Washington (1983) suggested that the similarity in absorption efficiency between barium sulfate and barium chloride may have been due to the ability of hydrochloric acid in the stomach to solubilize small quantities of barium sulfate. This is supported by the finding that barium carbonate in a vehicle containing sodium bicarbonate was poorly absorbed. The buffering capacity of sodium bicarbonate may have impaired the hydrochloric acid-mediated conversion to barium chloride.

The results of these studies suggest that soluble barium compounds or barium compounds that yield a dissociated barium ion in the acid environment of the upper gastrointestinal tract have similar absorption efficiencies. Therefore, an absorption rate up to 84% as described for barium can be assumed for barium bis(dihydrogenorthophosphate).

 

Inhalation:

According to ECHA (2014) guidance, particles with aerodynamic diameters below 100 µm have the potential to be inhaled. In a recent study report (Ahrens, 2016), the mean mass median aerodynamic diameter of barium bis(dihydrogenorthophosphate) was measured to be 31.85 µm. Therefore, barium bis(dihydrogenorthophosphate) particles can be inhaled, but will unlikely reach the alveolar region of the respiratory tract since they are not below 15 µm (ECHA, 2014). Besides, the substance is not lipophilic, therefore would not have the potential to be absorbed directly across the respiratory tract epithelium. However, its nature as physiological substance will probably lead to some absorption via the respiratory tract. Non-resorbed particles in the oral-nasal cavity, the airways and the lungs will be transferred to the gastro-intestinal tract with the mucus and absorbed there. Therefore absorption from the gastrointestinal tract will contribute to the total systemic burden of the substance that is inhaled.

In a study with barium chloride the absorption of labelled barium chloride (¹³³BaCl₂) solutions in 1-year-old Syrian hamsters was studied. Absorption into the general circulation of solutions deposited on nasal membranes was compared with gastrointestinal tract absorption. During the first 4 h after administration, barium absorption from the nasal passages was approximately 61%, compared with 11% gastric absorption. It was concluded that the nasopharynx is a major absorption site for inhaled aerosols of soluble barium, especially for readily soluble aerosols having mass median aerodynamic diameters > 5 µm (WHO, 1990).

On this basis, a default absorption for the inhalation route of 100% is proposed..

Dermal:

No data are available on dermal absorption of barium bis(dihydrogenorthophosphate). If no data is available, basic physico-chemical information should be taken into account, i.e. molecular mass and lipophilicity (log P) (ECHA, 2014). Following, a default value of 100% skin absorption is generally used unless molecular mass is above 500 and log P is outside the range [-1, 4], in which case a value of 10% skin absorption is chosen. This current approach to dermal absorption is conceived for organic chemical compounds. This concept is based on the hypothesis that an optimum in log Pow and a maximum in MW for facilitating percutaneous absorption exists. However, this approach is not considered particularly relevant for metals, for the following reasons:

• log Pow is a parameter that has no bearing whatsoever in the prediction of the properties of a metal or of an inorganic salt of a metal. This has already been recognised for organisms living in the environment, from which organic substances are transferred to biota via passive diffusion as predicted by Fick's Law. In contrast, most inorganic metal species do not permeate the membranes that separate organism from the external environment by passive diffusion. Instead, the uptake of metals largely depends on the presence of specific transport systems that provide biological gateways for the metal to cross the membrane.

• Conventional thinking on percutaneous transfer mechanisms assumes that dissolution of a compound is a prerequisite for subsequent (predominantly diffusion controlled) absorption mechanisms to take place. However, the dissolution of an inorganic metal compound or the metal itself on the skin surface will intrinsically require dissociation, and ultimately liberation of free metal cations.

• It is therefore obvious that the second criterion for assigning a dermal absorption rate (namely molecular weight) is irrelevant for metals, since under no circumstances it is feasible that any metal cation may exceed the cut-off value of “500“.

Therefore, for barium bis(dihydrogenorthophosphate) an approach consistent with the methodology proposed in HERAG guidance for metals is used:

In contrast to the default 10% or 100% values for substances with no further information, the currently available scientific evidence on dermal absorption of metals (predominantly based on the experience from previous EU risk assessments) yield substantially lower values as described subsequently:

Measured dermal absorption values for metals or metal compounds in studies corresponding to the most recent OECD test guidelines are typically 1% or even less. Therefore, the use of a 10% default absorption factor is not scientifically supported for metals. This is corroborated by conclusions from previous EU risk assessments (Ni, Cd, Zn), which have derived dermal absorption rates of 2% or far less (but with considerable methodical deviations from existing OECD methods) from liquid media - more recent and guideline-conform testing with refined accuracy has even yielded dermal absorption rates at or below 0.3% (Cu, Pb, Sb). Thus, on a preliminary basis, currently a default dermal absorption rate of 1% for absorption from liquid aqueous media would appear reasonable and adequately conservative for regulatory purposes based on a comparative assessment of the results from reliable, guideline-conform dermal absorption studies.

However, considering that under industrial circumstances many applications involve handling of dry powders, substances and materials, and since dissolution is a key prerequisite for any percutaneous absorption, a factor 10 lower default absorption factor may be assigned to such “dry” scenarios where handling of the product does not entail use of aqueous or other liquid media. This approach was taken in the EU RA on zinc. A reasoning for this is described in detail in Cherrie and Robertson, 1995, based on the argument that dermal uptake is dependent on the concentration of the material on the skin surface rather than it’s mass.

The following default dermal absorption factors for metal cations and thus for Ba²⁺ are therefore proposed:

From exposure to liquid/wet media: 1.0%

From dry (dust) exposure: 0.1 %

 

DISTRIBUTION:

No data were found regarding the distribution and metabolism for barium bis(dihydrogenorthophosphate). Looking at the physico chemical parameters of barium bis(dihydrogenorthophosphate) (MW > 100 g/mol, inorganic, soluble) a wide tissue distribution is not assumed (ECHA, 2014). But the structure suggests that barium bis(dihydrogenorthophosphate) will ionise to phosphate anions and barium cations. Phosphate is dissolved as ions in blood. The highest concentrations of barium in the body are found in the bone; approximately 91% of the total body burden is in the bone (WHO, 1990). In the bone, barium is primarily deposited in areas of active bone growth (WHO, 1990). The uptake of barium into the bone appears to be rapid. One day after rats were exposed to barium chloride aerosols, 78% of the total barium body burden was found in the skeleton; by 11 days post-exposure, more than 95% of the total body burden was found in the skeleton. The remainder of the barium in the body is found in soft tissues (i.e., aorta, brain, heart, kidney, spleen, pancreas, and lung) (WHO, 1990). McCauley and Washington (1983) found that 24 hours after administration of an oral dose of ¹³¹BaCl₂ to dogs, ¹³¹Ba levels in the heart were three times higher than the concentration in the eye, skeletal muscle, and kidneys (concentrations in the eye, muscle, and kidneys were similar). Additionally, the levels in the heart, eye, skeletal muscle, and kidneys were higher than the whole-blood concentration, suggesting the ability of soft tissue to concentrate barium.

 

METABOLISM:

Barium is not metabolized in the body, but it may be transported or incorporated into complexes or tissues.

EXCRETION:

The elimination of either injected or ingested barium in both humans and animals occur principally in the faeces rather than in the urine (WHO, 1990).

 

 

Cherrie and Robertson (1995): Biologically relevant assessment of dermal exposure; Ann. Occup. Hyg. 39, 387-392

HERAG (2007): HERAG fact sheet - assessment of occumpational dermal exposure and dermal absorption for metals and inorganic metal compounds;

EBRC Consulting GmbH / Hannover /Germany; August 2007; http://www.ebrc.de/downloads/HERAG_FS_01_August_07.pdf)

McCauley, PT; Washington, JS. (1983) Barium bioavailability as the chloride sulfate, or carbonate salt in the rat. Drug Chem Toxicol 6(2):209-217.

Stoewsand, GS; Anderson, JL; Rutzke, M; et al.(1988) Deposition of barium in the skeleton of rats fed Brazil nuts. Nutr Rep Int 38:259-262.

Taylor, DM; Pligh, PH; Duggan, MH.(1962) The absorption of calcium, strontium, barium and radium from the gastrointestinal tract of the rat.Biochem J 83:25-29.

World Health Organization (WHO). (1990) Environmental health criteria 107: barium. Sponsored by United Nations Environment Programme, International Labour Organisation, and World Health Organization. Geneva, Switzerland.