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Description of key information

In the absence of specific data regarding the toxikokinetic behaviour of Aluminium dihydrogen triphosphate, its physicochemical properties and relevant toxicity data (where available) were assessed for insights into likely ADME characteristics. Aluminium dihydrogen triphosphate has a molecular weight of 282.98 g/mol and a water solubility of 0.34 mg/L; therefore absorption via the dermal, inhalation and oral routes is anticipated to be low. The data paucity dictates a precautionary approach and thus a default value of 100% absorption is considered appropriate for oral and inhalation exposure in the absence of any additional data. Dermal absorption is likely to be low and a default value of 10% isconsidered for dermal absorption. There are no substance-specific data regarding distribution and metabolism but the body is likely to handle any absorbed material in the same way that it normally deals with aluminium and phosphate compounds. Following ingestion, unabsorbed aluminium dihydrogen triphosphate will be excreted in the faeces. Any absorbed material is likely to be excreted in the urine. 

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Aluminium dihydrogen triphosphate (CAS 13939-25-8) 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.

Aluminium dihydrogen triphosphate is a solid at 20°C with a molecular weight of 282.89 g/mol and a water solubility of 0.34 mg/L (O’Conner & Wooly, 2009). The estimated vapour pressure is calculated to be 1E-8 Pa at 20 °C (CHESAR 2.3).

 

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 dihydrogen triphosphate is an inorganic substance a log Pow cannot be determined because it is neither soluble in water nor in octanol.

Oral

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). Lipophilic compounds may be taken up by micellar solubilisation by bile salts, but this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) as these would otherwise be poorly absorbed (Aungst and Shen, 1986; ECHA, 2014).

With a low aqueous solubility, oral absorption is expected to be low (as is typical for aluminium salts (ATDSR, 2008)). For a substance to be absorbed efficiently from the gastrointestinal tract it must be in solution. Aluminium dihydrogen triphosphate is “essentially insoluble” in water and therefore not expected to readily dissolve in the gastrointestinal fluids (O’Connor & Woolley, 2011; ECHA, 2014). However, ECHA guidance suggests that absorption is considered favourable for substances with a molecular weight (MW) below 500 Daltons (ECHA, 2014). Thus, based on this assumption, the MW (282.89 g/mol) might be indicative of absorption.In addition, considering that aluminium and phosphate ions might be released from Aluminium dihydrogen triphosphate 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).

Moreover, a study on acute oral toxicity withAluminium dihydrogen triphosphateshowed no signs of systemic toxicity resulting in a LD50 value > 2000 mg/kg bw (Bradshaw, 2012). Furthermore, available data on subchronic oral toxicity of 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 administeredAluminium dihydrogen triphosphate or its breakdown products are systemically available.

Overall, in the absence of specific data, and given the possibility that solubility in gastric fluid may be higher than in water and that systemic effects were 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 dihydrogen triphosphate. On the basis of the following considerations, the dermal absorption of the substance is considered to be low.

In respect of dermal absorption, the MW (282 g/mol) indicates possible absorption via the skin. For a compound to penetrate the stratum corneum, it must be sufficiently water soluble i.e. above 1 mg/L. Thus, based on the low water solubility (<0.34 mg/L) dermal uptake is likely to be very low.

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 dihydrogen triphosphat showed no irritating effects (Warren, 2012).

Overall, taking into account the physico-chemical properties of Aluminium 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 anda default of 10% is tentatively suggested for dermal absorption.

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). However, due to aluminium dihydrogen triphosphate’s low water solubility, the rate at which the particles dissolve into the mucous fluid will limit the amount that can be absorbed directly. Furthermore, it is known that aluminium is poorly absorbed following inhalation exposure (ATSDR, 2008). In a recent study report, the aerodynamic diameter of aluminium dihydrogen triphosphate ranged from 0.46-9.7 µm with a mean mass median aerodynamic diameter of 3.31 µm (Griffiths, 2012). Based on its aerodynamic diameter, Aluminium dihydrogen triphosphate may reach the alveolar region of the respiratory tract (ECHA, 2014).

Poorly water-soluble and poorly lipid-soluble particles (i.e. water solubility of 1 mg/L or less, Log P values around 0) with aerodynamic diameters below 10 µm have the potential to deposit in the alveolar region of the lung. Aluminium dihydrogen triphosphate is of low water solubility and, with reference to the recent study, approximately one third of aluminium dihydrogen triphosphate particles were below 1 µm (Griffiths, 2012). Hence, aluminium dihydrogen triphosphate may possess the potential to accumulate in the lung. Once deposited, alveolar macrophages are likely to engulf the particles and subsequently would either translocate the particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues; slow absorption may occur (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 dihydrogen triphosphate. Since the substance is of low solubility, it will not be able to diffuse through aqueous channels and pores (ECHA, 2014). However, partial release of aluminium cations and phosphate anions is considered possiblefollowing 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 dihydrogen triphosphate 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 mammales: 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

Anane R, Bonini M, Creppy EE. 1997. Transplacental passage of aluminum from pregnant mice to fetus organs after maternal transcutaneous exposure. Hum Exp Toxicol 16(9):501-504.

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.

Aungst B. and Shen D.D. (1986). Gastrointestinal absorption of toxic agents. In Rozman K.K. and Hanninen O. Gastrointestinal Toxicology. Elsevier, New York, US.

ECHA (2014). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Version 2.0, November 2014

Elinder CG, Ahrengart L, Lidums V, et al. 1991.Evidence of aluminum accumulation in aluminum welders. Br J Ind Med 48(11):735-738.

Ganrot, P.O. (1986). Metabolism and possible health effects of aluminum. Environ Health Perspect 65:363-441.

Golub MS, Han B, Keen CL. 1996. Developmental patterns of aluminum and five essential mineral elements in the central nervous system of the fetal and infant guinea pig. Biol Trace Elem Res 55(3): 241-251

Greger JL, Baier MJ. 1983. Excretion and retention of low or moderate levels of aluminum by human subjects. Food Chem Toxicol 21(4):473-477.

Greger JL, Radzanowski GM. 1995. Tissue aluminium distribution in growing, mature and ageing rats: relationship to changes in gut, kidney and bone metabolism. Food Chem Toxicol 33(10):867-875

Jouhanneau P, Raisbeck GM, Yiou F, et al. 1997. Gastrointestinal absorption, tissue retention, and urinary excretion of dietary aluminum in rats determined by using 26Al. Clin Chem 43(6 Part 1):10231028.

Krewski, et al. (2007).Human Health Risk Assessment for Aluminium, Aluminium Oxide, and Aluminium Hydroxide, A Report Submitted to theEnvironmental Protection Agency. J Toxicol Environ Health B Crit Rev. 10 Suppl 1:1-269.

Steinhausen C, Kislinger G, Winklhofer C, et al. 2004. Investigation of the aluminum biokinetics in humans: A 26Al tracer study. Food Chem Toxicol 42(3):363-371.

Wilhelm M, Jager DE, Ohnesorge FK. 1990. Aluminum toxicokinetics. Pharmacol Toxicol 66:4-9.

Yokel RA, McNamara PJ. 2001. Aluminium toxicokinetics: An updated minireview. Pharmacol Toxicol 88(4):159-167.

Yumoto S, Nagai H, Matsuzaki H, et al. 2000. Transplacental passage of 26Al from pregnant rats to fetuses and 26Al transfer through maternal milk to suckling rats. Nucl Instrum Methods Phys Res B 172:925-929.