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Administrative data

Link to relevant study record(s)

Description of key information

Phosphoric acid alkyl esters are expected to undergo hydrolysis by phosphatases, e.g. acid phosphatase or alkaline phosphatise, to aliphatic alcohols and Phosphoric acid in the gastrointestinal tract. 
Dermal absorption of Phosphoric acid alkyl esters can be assumed to be <10%.
Phosphate as such is not metabolised, but is an essential dietary constituent, which is involved in numerous physiological processes. Linear and branched 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. Branched aliphatic chains can be degraded via alpha- or omega-oxidation.
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
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
100

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 SIDSInitial Assessment Reporton 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).

 “Net absorption from a mixed diet has been reported to vary between 55-70% in adults (Lemann 1996; Nordin, 1986) and between 65-90% in infants and children (Ziegler and Fomon, 1983). There is no evidence that, contrary to calcium, absorption efficiency varies with dietary intake. Phosphate absorption is greatest in jejunum and takes place by a saturable, active transport mechanism, facilitated by 1,25-dihydroxyvitamin D, as well as by passive diffusion (Chenet al., 1974).” (EFSA, 2005)

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 aChemical 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). Based on that, the maximum steady state penetration rate of the registered substance will be lower than 0.01mg/cm²/h.

 

No data are available on the dermally absorbed fraction of Phosphoric acid alkyl esters. Thus, a QSAR model (IH Skin Perm, ten Berge, 2009; Wilschut et al, 1995) was used to estimate the dermal absorption. This QSAR estimates dermal absorption based on molecular weight, water solubility, n-octanol-water partition coefficient (log Kow), vapour pressure and density. The physicochemical parameters needed for IH Skin Perm (log Kow, water solubility, vapour pressure) have been calculated with EpiSuite 4.1.

 

Substance

Fraction absorbed [%]

Maximum dermal absorption [mg/cm²/h]

Monohexadecyl phosphate

0.30%

1.20E-04

Dihexadecyl phosphate

0.00%

5.20E-06

Monooctadecyl phosphate

0.10%

3.70E-05

Dioctadecyl phosphate

0.20%

6.44E-05

Monoisododecyl phosphate

4.40%

1.82E-03

Monoisotridecyl phosphate

2.50%

1.04E-03

 

The model does not take into account ionisation of the substances. Thus, the real absorbed fractions may be even lower (see Guidance on information requirements and chemical safety assessment, Chapter R.7c). Based on these information it can be assumed that the dermal absorption of Phosphoric acid alkyl esters can be assumed to be <10%.

 

Distribution

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

According to EFSA (2005) “approximately 70% is present as organic phosphates, such as in the phospholipids of red blood cells and in the plasma lipoproteins. The other 30% is present as inorganic phosphate, of which 15% is protein bound. About 50% of the inorganic phosphate is in the soluble divalent cation form (HPO42-), the remaining as the monovalent anion (H2PO4-, 10%) and the trivalent cation (PO43-, <0.01%), or as HPO42-complexed with sodium, calcium and magnesium salts. These anion forms are interconvertible and effective buffers of blood pH and involved in regulation of the whole body acid-base balance.

[…]

Serum Pi [= inorganic phosphate] in normal adults varies between 0.97-1.45 mmol/L (3.0-4.5 mg/dL), and shows a slight increase with increasing phosphorus intakes (Heaney, 1996). Hyperphosphatemia, associated with clear clinical symptoms, has only been reported in patients with end-stage renal disease, i.e. when glomerular filtration rate (GFR) has decreased below 20% of the adult value (FNB, 1997).” (EFSA, 2005)

“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).

 

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).

Phosphate as such is not metabolised. It “is an essential dietary constituent, involved in numerous physiological processes, such as the cell’s energy cycle (high-energy pyrophosphate bonds in adenosine triphosphate [ATP]), regulation of the whole body acid-base balance, as component of the cell structure (as phospholipids) and of nucleotides and nucleic acids in DNA and RNA, in cell regulation and signalling by phosphorylation of catalytic proteins and as second messenger (cAMP). Another important function is in the mineralization of bones and teeth (as part of the hydroxyapatite)” (EFSA, 2005).

Linear and branched 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. Branched aliphatic chains can be degraded via alpha- or omega-oxidation (see common text books on biochemistry).

“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) (Kabir, 1993; 1995a,b).

A comparison of the linear and branched aliphatic alcohols shows a high degree of similarity in biotransformation. For both sub-categories the first step of the biotransformation consists of an oxidation of the alcohol to the corresponding carboxylic acids, followed by a stepwise elimination of C2 units in the mitochondrialβ-oxidation process. The metabolic breakdown for both the linear and mono-branched alcohols is highly efficient and involves processes for both sub-groups of alcohols. The presence of a side chain does not terminate theβ-oxidation process, however in some cases a single Carbon unit is removed before the C2 elimination can proceed.” (OECD SIDS, 2006)

 

Excretion

The metabolites of Phosphoric acid alkyl esters - Phosphate and aliphatic alcohols, which are oxidised to the corresponding fatty acids - enter normal metabolic pathways and are therefore indistinguishable from Phosphate and lipids from other sources. Phosphate levels are regulated by parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D. Excess absorbed Phosphate is renally excreted (EFSA, 2005).

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

 

References

EFSA (2005) Opinion of the Scientific Panel on Dietetic Products, Nutrition and Allergies on a request from the Commission related to the Tolerable Upper Intake Level of Phosphorus, The EFSA Journal (2005) 233, 1-19; available via internet:http://www.efsa.europa.eu/en/efsajournal/doc/233.pdf

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:http://www.gezondheidsraad.nl/sites/default/files/00@15OSH158.pdf

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

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

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

ten Berge WF. (2009). A simple dermal absorption model: Derivation and application. Chemosphere 75, 1440-1445

Wilschut, A., ten Berge, W. F., Robinson, P. J., McKone, T. E. (1995) Estimating skin permeation. The Validation of five mathematical skin permeation models.Chemosphere 30, 1275-1296http://home.planet.nl/~wtberge/qsarperm.html