Aluminium tris(dihydrogen phosphate)

Endpoint summary

Description of key information

No toxicokinetic studies exist, therefore an assessment of basic toxicokinetics has been made based on the available data. 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

 Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of aluminium tris(dihydrogen phosphate) 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 Aluminium dihydrogen triphosphate 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) and taking into account further available information on structural analogue substances. Aluminium compounds were considered for this approach, since the pathways leading to toxic outcomes are dominated by the chemistry and biochemistry of the aluminium ion (Al3+) (Krewski et al., 2007; ATSDR, 2008). Moreover, phosphate anions belong to naturally occurring ions present in nearly all tissues and organs of mammals. Thus, the phosphate components of the source and target substances are not discussed within this statement as they are not considered to be toxicologically relevant.

Aluminium tris(dihydrogen phosphate) is a solid at 20°C with a molecular weight of 318 g/mol and a water solubility of 294 g/L (O’Conner & Woolley, 2010). The estimated vapour pressure is assumed to be 1 x 10-6 Pa at 20°C. A partition coefficient cannot be derived as the substances are inorganic, highly ionised and extremely water soluble. Solubility in fat or organic solvents is negligible. Therefore the passive dissociation across biological membranes will be negligible. For details of uptake, see below.

 

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. Since aluminium tris(dihydrogen phosphate) is an inorganic substance a log Pow cannot be determined because it is neither soluble in water nor in octanol.

Oral

There are no data specifically regarding the oral absorption of aluminium tris(dihydrogen phosphate).

In general, molecular weights below 500 and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L).

The molecular weight (318 g/mol) might be indicative of absorption. In addition, considering that aluminium and phosphate ions might be released from aluminium tris(dihydrogen phosphate) following chemical or biological hydrolysis, passage through aqueous pores or carriage of ionic species with passaging water might facilitate absorption of water-soluble molecules like aluminium ions (ECHA, 2012). However, common biological ligands are known to either increase or decrease the bioavailability of aluminium from various sources. The main process is probably passive paracellular diffusion, but also interaction with calcium uptake through specific channels is reported (WHO, 2007). The absorption of aluminium from aluminium phosphates is approximately 0.1 % as shown by Yokel RA (2006) for rats with acidic SALP. Under basic conditions in the gut, monoaluminium orthophosphate is formed, which shows slight solubility of 19.7 mg/L under these conditions. This effect very likely limits bioavailability of aluminium from aluminium phosphates. Further, phosphate is known to decrease the bioavailability of aluminium (EFSA, 2008).

It could be argued that as the EFSA reports that the oral bioavailability of aluminium from drinking water is 0.3% and from food/drinks is 0.1% the oral bioavailability from aluminium tris(dihydrogen phosphate) could be < 10%. Further, a new study on the bioavailability of aluminium from several aluminium compounds in rats was conducted in 2011 and reviewed by EFSA (EFSA, 2011). This data confirmed the findings of the original EFSA review as reported above.

A study on acute oral toxicity with aluminium tris(dihydrogen phosphate) showed no signs of systemic toxicity resulting in a LD50 value > 2000 mg/kg bw (Bradshaw J, 2010). Available data on sub-chronic oral toxicity of analogous aluminium salt (aluminium dihydrogen triphosphate) showed some systemic effects in highest dose group resulting in a NOAEL of 300 mg/kg bw/day (Sunaga, 2002). Hence, existing systemic toxicity of the substance indicates that at least a part of administered aluminium tris(dihydrogen phosphate) or its breakdown products could be systemically available.

Overall, in the absence of specific data and systemic effects observed after repeated treatment an oral absorption of 100% as default value should be considered as worst case assumption.

Dermal

There are no data available on dermal absorption or on acute dermal toxicity of aluminium tris(dihydrogen phosphate). On the basis of the following considerations, the dermal absorption of the substance is considered to be low.

Considerations of molecular weight and LogPow do not apply to metals as inorganic compounds require dissociation to metal cations prior to being able to penetrate the dermis. As metal ions have an inherent reactivity towards protein structures the likelihood of them penetrating the skin is reduced. It is therefore anticipated that the following default dermal absorption factors be used for metal cations (ICCM, 2007):

- From exposure to liquid / wet material: 1%

- From dry (dust) exposure: 0.1%

In addition, as the test substance is a solid, hindered dermal absorption has to be considered as dry particulates first have to dissolve into the surface moisture of the skin before uptake via the skin is possible (ECHA, 2014).

Moreover, the in vitro irritation skin studies performed with aluminium tris(dihydrogen phosphate) showed no irritating or corrosive effects (Warren, 2010).

Overall, taking into account the physico-chemical properties of aluminium tris(dihydrogen triphosphate), available toxicological data and that aluminium is essentially not absorbed dermally (ATSDR, 2008) the dermal absorption potential of the substance is anticipated to be low and a default of 10% is tentatively suggested for dermal absorption as a worst-case.

Inhalation

A default value of 100% inhalation absorption is usually applied. Very hydrophilic substances might be absorbed through aqueous pores (MW <200) or be retained in the mucous and transported out of the respiratory tract (ECHA, 2014). It is known that aluminium is poorly absorbed following inhalation exposure (ATSDR, 2008). Based on its aerodynamic diameter, aluminium tris(dihydrogen phosphate) may reach the alveolar region of the respiratory tract (ECHA, 2014).

 

Distribution

Distribution of a compound within the body depends on the physico-chemical properties of the substance; especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution (ECHA, 2014).

No data are available regarding the distribution and metabolism of aluminium tris(dihydrogen phosphate). Partial release of aluminium cations and phosphate anions is considered possible following chemical or biological hydrolysis. Presumably, any absorbed material will be handled in the same way as other absorbed aluminium and phosphate compounds (including certain food additives e.g. sodium aluminium phosphate).

Aluminium distributes unequally to all tissues throughout normal and aluminium-intoxicated human beings and aluminium-treated experimental animals. Growing, mature and ageing rats differed in regard to the initial distribution of aluminium in their tissues after a large oral dose (Greger and Radzanowski 1995). Within blood, aluminium is approximately equally distributed between plasma and cells. The higher concentration in lung of normal humans may reflect entrapment of airborne aluminium particles, whereas the higher concentrations in bone, liver and spleen may reflect aluminium sequestration. The skeletal system and lung have ~50 and 25% of the 30-50 mg aluminium body burden of the normal human; brain has ~1%. Considering the aluminium species in plasma, it is likely that aluminium transferrin and aluminium citrate account for the majority of the aluminium that distributes to tissues from the vascular compartment.

The brain has lower aluminium concentrations than many other tissues. Increased brain aluminium is seen in aluminium-associated neurotoxicity in humans. Aluminium can enter the brain from blood. Dietary aluminium in guinea pigs led to elevated aluminium concentrations in brain regions, highest in spinal cord, brainstem, and cerebellum, and decreased during late gestation and lactation (Golub et al. 1996). There is evidence that transferrin can mediate aluminium transport across the blood-brain barrier by transferrin-receptor mediated endocytosis of aluminium-transferrin, the predominant aluminium species in plasma. A second mechanism transporting aluminium citrate across the blood-brain barrier into the brain is suggested that is independent of transferrin (too fast to be receptor-mediated). There appears to be a mechanism to transport aluminium out of the brain. It is likely that aluminium citrate is the aluminium species transported out of the brain.

Bone aluminium concentration in normal human beings is a few times greater than brain aluminium. In humans, the largest long-term deposition of aluminium occurs in the bones (Steinhausen et al 2004). Several animal studies showed ~100 times higher bone than brain26Al concentrations after a single26Al dose, suggesting greater aluminium entry into bone than brain. Aluminium concentrates at the mineralization front of bone (Yokel and McNamara 2001). About 50% of absorbed aluminium is rapidly (< 2 hours) and permanently accumulated in the skeleton of young rats (Jouhanneau et al. 1997). In rats, a single gavage treatment with26Al, showed that the fraction absorbed retained in the skeleton (0.025 -0.030%) was of the same order of magnitude as the fraction excreted in the 48 hour urine (0.035 -0.037%). Furthermore, it was shown that26Al administered to pregnant rats and/or lactating rats is transferred to their offspring through transplacental passage and/or maternal milk (Yumoto et al. 2000).

Skin exposure to aluminium chloride produced a significant increase of aluminium accumulation in the brain, especially in the hippocampal area. This finding was confirmed by microanalysis on slices of hippocampus showing accumulation of aluminium silicates (Anane et al. 1995). Cutaneous aluminium uptake in mice also led to an increase of aluminium in maternal and fetal samples (serum, amniotic fluid and organs) as compared to controls (Anane et al. 1997). However, as mentioned above, oral exposure through grooming cannot be excluded.

 

Metabolism

Aluminium tris(dihydrogen phosphate) is an inorganic substance. Therefore, metabolic transformation will not take place within the human body.

However, at least partial release of aluminium cations and phosphate anions following chemical or biological hydrolysis is considered possible. Four different chemical forms of aluminium are known within mammals: 1) free ions, 2) low-molecular-weight complexes, 3) physically bound macromolecular complexes, and 4) covalently bound macromolecular complexes (Ganrot 1986). Metabolism of aluminium depends on its binding affinity to ligands and finally to their metabolism. Phosphate anions are present in nearly all tissues and organs of mammals as they are essential for cellular survival and activity. Thus, regulated uptake of the phosphate component is considered. In general, phosphate will be incorporated in diverse catabolic processes to form physiological organic phosphates, including DNA/RNA, phosphatidyl inositol and adenosine triphosphate.

 

Excretion

In general, it is accepted that aluminium is mainly excreted in urine, while unabsorbed aluminium is excreted primarily in the faeces. In humans, 0.09 and 96% of the aluminium intake per day was cleared through the urine and faeces, respectively, during exposure to 1.71 mg Al/kg/day as aluminium lactate in addition to 0.07 mg Al/kg/day in basal diet for 20 days (Greger and Baier 1983). In rats, about 50% of absorbed aluminium is excreted in urine, with 90% of this excretion occurring during the first 48 hours after ingestion. Nevertheless, there is evidence that aluminium can also be eliminated via the bile. Biliary aluminium excretion accounted for only 0.1% of the total aluminium load, whereas 37% was renally excreted. Similar results were obtained in rats. It seems that under certain pathophysiological conditions biliary aluminium excretion is altered (Wilhelm et al. 1990).

Elimination half-lives in the range of years were seen after termination of occupational aluminium exposure, based on urinary aluminium excretion. This kinetic behaviour might result from retention of aluminium in a depot from which it is slowly eliminated. This depot is probably bone which stores ~50% of the human aluminium body burden (Elinder et al. 1991). Brain, serum and bone aluminium have been reported to increase with age. Aluminium clearance from bone is more rapid than from the brain, which is reasonable considering bone turnover and lack of neurone turnover. Urine accounts for > 95% of excreted aluminium. Reduced renal function increases the risk of aluminium accumulation and toxicity in the very young, elderly and renally diseased human being. In rats, the half-life of aluminium in tissues was also affected by age. Ageing rats retained aluminium much longer in tibias than mature and growing rats. Also ageing and mature rats retained aluminium longer in kidneys than growing rats (Greger and Radzanowski 1995). Chelators and citrate can increase aluminium clearance into urine, bile and dialysate (Yokel and McNamara 2001).

 

References not in IUCLID

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Anane R, Bonini M, Grafeille MJ, et al. 1995.Bioaccumulation of water soluble aluminum chloride in the hippocampus after transdermal uptake in mice. Arch Toxicol 69(8):568-571.

ATSDR (Agency for Toxic Substances and Disease Registry) (2008).Toxicological Profile for Aluminum.Atlanta,:Department of Health and Human Services, Public Health Service.

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EFSA (2008) Safety of aluminium from dietary intake. Scientific Opinion of the Panel on Food Additives, Flavourings, Processing Aids and Food Contact Materials (AFC). The EFSA Journal. 754: 1-34

EFSA (2011) Statement of EFSA. On the evaluation of a new study related to the bioavailability of aluminium in food. European Food Safety Authority. The EFSA Journal. 9(5):2157

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ICMM (2007) HERAG: Health Risk Assessment Guidance for Metals 

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