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Description of key information

Data from in vitro or in vivo studies, which were designed to identify the toxicokinetic properties of Phosphoric acid, C12-18-alkyl esters, potassium salts, are not available.

Phosphoric acid alkyl esters are expected to undergo hydrolysis by unspecific phosphatases, e.g. Acid phosphatase or Alkaline phosphatase to aliphatic alcohols and Phosphoric acid in the gastrointestinal tract. Both enzymes are found in most organisms from bacteria to human.

Phosphate as such is not metabolised, but is an essential dietary constituent, which is involved in numerous physiological processes. Linear primary aliphatic alcohols are oxidized to the corresponding carboxylic acid, with the corresponding aldehyde as a transient intermediate. The carboxylic acids are further degraded via acyl-CoA intermediates in by the mitochondrial beta-oxidation process.

The metabolites of Phosphoric acid alkyl esters enter normal metabolic pathways and are therefore indistinguishable from Phosphate and lipids from other sources.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Absorption

Oral absorption

Phosphoric acid alkyl esters are expected to undergo hydrolysis to aliphatic alcohols and Phosphoric acid in the gastro-intestinal tract by intestinal phosphatases. Thus, the gastro-intestinal absorption of Phosphoric acid alkyl esters is assumed to play a minor role compared to the absorption of the metabolites aliphatic alcohols and Phosphoric acid.

This is supported by data collected by the Dutch Committee on Updating of Occupational Exposure Limits on Tributyl Phosphate (Health Council of the Netherlands, 2005): “After administration of oral doses of tributyl phosphate of 156 mg/kg bw, the parent compound was detected in the gastrointestinal tract, the blood, and the liver within 30 to 60 minutes. Following a single dose, the highest amount was found in the gastrointestinal tract (not quantified), and 5.7% of the dose was detected in the other tissues (no further information given).”

Long chain aliphatic alcohols can be expected to be orally absorbed depending on their chain-length. As stated in the OECD SIDS Initial Assessment Report on long chain alcohols, aliphatic alcohols “orally administered aliphatic alcohols […] show a chain-length dependant potential for gastro-intestinal absorption, with shorter chain aliphatic alcohols having a higher absorption potential than longer chain alcohols.” (OECD SIDS, 2006)

Phosphate is an essential nutrient which is absorbed in the small intestine via passive diffusion (paracellular transport) as well as via active transport by sodium-dependent phosphate co-transporters (Sabbagh et al, 2011).

“Phosphorus is absorbed with high efficiency. In adults, net phosphorus absorption typically ranges from 55 to 80 % of customary intakes, and in infants from 65 to 90 % (Heaney, 2012; O'Brien et al., 2014). Intestinal phosphorus absorption tends to decrease with ageing. […]

There are two pathways for intestinal absorption of inorganic phosphorus, i.e. paracellular and cellular (Sabbagh et al., 2011; Penido and Alon, 2012), and at least two mechanisms, i.e. passive diffusion (McHardy and Parsons, 1956) and sodium-dependent active transport (Walton and Gray, 1979; Eto et al., 2006). Most phosphorus absorption occurs in the small intestine by load-dependent passive absorption.” […]

“The ability to absorb and use phosphorus is affected by the total amount of phosphorus in the diet and also by the type of phosphorus (organic versus inorganic), the food origin (animal- versus plant-derived) and the ratio of phosphorus to other dietary components. […]

The principal factor influencing phosphorus absorption is co-ingested calcium, which binds phosphorus in the digestive chime, thereby preventing its absorption (Heaney, 2012; O'Brien et al., 2014).” (EFSA 2015)

 

The oral absorption of Phosphoric acid alkyl esters and their metabolites is considered to be 100%.

 

Dermal absorption

The maximum steady state penetration rate (which is the highest exposure risk for a chemical) of Phosphoric acid alkyl esters and Phosphoric acid were predicted from in vitro measurements by Marzulli et al. (1965), also cited in a Chemical Hazard Information Profile on Tri(alkyl/alkoxy) Phosphates by Sigmon and Daugherty, 1985:

Substance

Dermal penetration rate µg/cm²/min

Dermal penetration rate recalculated to mg/cm²/h

Trimethyl phosphate

1.47

0.0882

Triethyl phosphate

1.12

0.0672

Tri(isopropyl) phosphate

0.78

0.0468

Tri-n-propyl phosphate

0.65

0.039

Tri-n-butyl phosphate

0.18

0.0108

Phosphoric acid, 8.5%

0.003

0.00018

 

In human the average maximum steady state rate of penetration of Tri-n-butyl phosphate through the anterior forearm skin was 0.10 μg/cm²/min (= 0.006 mg/cm²/h). No further details are available (Marzulli et al., 1965).

From these data it can be concluded, that the dermal penetration rate of Phosphoric acid alkyl esters decreases with increasing chain length. It can be further assumed that ionised forms as Phosphoric acid mono- and dialkyl esters have a lower dermal penetration rate than Phosphoric acid trialkyl esters (see Guidance on information requirements and chemical safety assessment, Chapter R.7c).

 

 

Distribution

As Phosphoric acid alkyl esters are assumed to be efficiently hydrolysed by unspecific phosphatases, to aliphatic alcohols and Phosphate, the distribution of the parent compound does not play a major role.

“The long chain aliphatic carboxylic acids are efficiently eliminated and aliphatic alcohols are therefore not expected to have a tissue retention or bioaccumulation potential (Bevan, 2001). Longer chained aliphatic alcohols within this category may enter common lipid biosynthesis pathways and will be indistinguishable from the lipids derived from other sources (including dietary glycerides)” (OECD SIDS, 2006).

According to EFSA (2015) “Phosphorus, as phosphate, is the most abundant anion in the human body and comprises approximately 1 % of total body weight (Farrow and White, 2010; Penido and Alon, 2012). Approximately 85 % of phosphorus is present in bones and teeth, with the remainder distributed among other tissues (14 %) and extracellular fluid (1 %) (O'Brien et al., 2014). Thus, like calcium (although more pronounced), serum measurements reflect only a minor fraction of total body phosphorus, and therefore do not consistently reflect total body stores (Moe, 2008).” (EFSA, 2015)

 

Metabolism

Phosphoric acid alkyl esters are hydrolysed unspecifically by phosphatases, e.g. acid phosphatase or alkaline phosphatase. Both enzymes are found in most organisms from bacteria to human. Alkaline phosphatases are present in all tissues, but are particularly concentrated in liver, kidney, bile duct, bone, placenta. In human and most other mammals three isoenzymes of Alkaline phosphatase exist: intestinal ALP, placental ALP, tissue non-specific ALP (present in bone, liver, kidney, skin).

Seven different forms of Acid phosphatase are known in humans and other mammals. These are also present in different tissues and organs (predominantly erythrocytes, liver, placenta, prostate, lung, pancreas).

Linear primary aliphatic alcohols are oxidised to the corresponding carboxylic acid, with the corresponding aldehyde as a transient intermediate. The carboxylic acids are further degraded via acyl-CoA intermediates in by the mitochondrial beta-oxidation process. (see common text book on biochemistry).

Phosphate as such is not metabolised. It “is an essential nutrient and is involved in many physiological processes, such as in the cell’s energy cycle, in regulation of the body’s acid–base balance, as a component of the cell structure, in cell regulation and signalling, and in the mineralisation of bones and teeth.” […)

“About 85 % of the body’s phosphorus is in bones and teeth, in the form of hydroxyapatite.” […]

Furthermore, “phosphorus present in the body is integral to diverse functions ranging from the transfer of genetic information to energy utilisation. Phosphorus is a structural component of the nucleic acids DNA and RNA and thus is involved in the storage and transmission of genetic material.” As well it is “an integral component of adenosine triphosphate (ATP), the body’s key energy source.”

 

Excretion

The metabolites of Phosphoric acid alkyl esters, Phosphate and aliphatic alcohols, enter normal metabolic pathways and are therefore indistinguishable from Phosphate and lipids from other sources.

 “Aliphatic alcohols are absorbed by all common routes of exposure, widely distributed within the body and efficiently eliminated. There is a limited potential for retention or bioaccumulation for the parent alcohols and their biotransformation products.” (OECD SIDS, 2006)

Phosphate levels are regulated by parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D.

 

“The kidney plays a predominant role in the regulation of systemic phosphorus homeostasis. About 80 % of filtered phosphorus is reabsorbed in the proximal tubule.” […] “Under normal conditions, about 15 % of the filtered phosphorus is ultimately excreted (Bindels et al., 2012).”

[…] “Total faecal phosphorus, however, represents both non-absorbed phosphorus from food, and losses of endogenous phosphorus. The latter are mainly derived from digestive secretions that have not been reabsorbed.” (EFSA, 2015)

 

In conclusion, a detailed examination of the excretion pathways seems not necessary.

 

References

EFSA (2015) Scientific Opinion on Dietary Reference Values for phosphorus, EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), EFSA Journal 2015;13(7):4185; available at:https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2015.4185

Health Council of the Netherlands: Committee on Updating of Occupational Exposure Limits. Tributyl phosphate; Health-based Reassessment of Administrative Occupational Exposure Limits. The Hague: Health Council of the Netherlands, 2005; 2000/15OSH/158; available via internet:https://www.healthcouncil.nl/documents/advisory-reports/2005/12/05/tributyl-phosphate

OECD SIDS, 2006 SIDS Initial Assessment Report for SIAM 22, Long Chain Alcohols (C6-22 primary aliphatic alcohols), available via internet:http://www.aciscience.org/docs/SIDS_LCA_tome2.pdf

Marzulli FN, Callahan JF, Brown DWC (1965) Chemical structure and skin penetrating capacity of a short series of organic phosphates and phosphoric acid.

Sabbagh Y, Giral H, Caldas Y, Levi M and Schiavi SC, 2011. Intestinal phosphate transport.

Sigmon CF, Daugherty ML (1985) Chemical Hazard Information Profile, Draft Report, Tri(alkyl/alkoxy) Phosphates, September 23, 1985, Report of Oak Ridge National Laboratory to US EPA; available via internet:http://nepis.epa.gov/Adobe/PDF/91005XP6.PDF