Phosphoric acid C12-alkyl and C18-alkyl esters, potassium salts

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert Statement

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert Statement, no study available

Objective of study:

absorption

distribution

excretion

metabolism

Details on species / strain selection:

not applicable

Details on test animals or test system and environmental conditions:

not applicable

Details on exposure:

not applicable

Duration and frequency of treatment / exposure:

not applicable

No. of animals per sex per dose / concentration:

not applicable

Positive control reference chemical:

not applicable

Details on study design:

not applicable

Details on dosing and sampling:

not applicable

Statistics:

not applicable

Details on absorption:

Generally, the smaller the molecule the more easily it may be taken up via oral route. Oral absorption is favoured for substances with a molecular weight below 500 g/mol. Substances with molecular weights above 1000 g/mol do not favour absorption. The molecular weight of the substance ranges from 304 to 641 g/mol. Therefore based on molecular weight the substances may be absorbed after oral intake. The water solubility / critical micelle concentration (55 mg/L) and the moderate log Pow-values (0.51) further support oral absorption. However, the available study data on acute oral toxicity (read across to C12 and C18-ester) do not support this assumption, as no deaths occurred and apart from piloerection no signs of (test item-related) systemic toxicity were noted up to the test concentration of 2000 mg/kg bw. Furthermore, no systemic effects were revealed in the OECD 422 study conducted with the read across-substance phosphoric acid, dodecyl ester, sodium salt up to the highest test concentration of 1000 mg/kg bw. The NOEL for male animals of 125 mg/kg bw/d and a NOEL for female animals of 62.5 mg/kg bw/d was determined based on local effects on the gastrointestinal mucosa due to the irritative nature of the test item. In a study according to OECD 421 conducted with the read across-substance Hexadecyl dihydrogen phosphate, there were also no signs of systemic toxicity observed up to the highest concentration of 1000 mg/kg bw.
The substance has a low volatility (low vapour pressure) and is not likely to become available as a vapour.
As the substance has a local effect on skin, damage to skin surface may enhance penetration. But, due to the water solubility of 55 mg/L absorption is anticipated to be low. Besides that, the log Pow of 0.51 indicates that penetration into the stratum corneum is limited. By using Dermwin v2.02 the Kp value of one read across-substances (Phosphoric acid, dodecyl ester, potassium salt, CAS 39322-78-6) was estimated to be 0.00203 cm/h, indicating that dermal uptake is low.

Details on distribution in tissues:

In general, the smaller the molecule the wider the distribution. The target and source substances show a molecular weight between 210 and 641 g/mol. Available study data with the substance itself or the read across-substances do not reveal target organs/tissues that could be taken as proof of distribution into a specific compartment or organ. It is assumed that after oral uptake the test substance will be metabolised in the GI tract and excreted. The log Pow value of 0.51 does further not imply a bioconcentration potential of the substance. The available study data revealed no indications of the substance to cross the blood-brain barrier.

Details on excretion:

The remaining phosphates are excreted via urine.

Details on metabolites:

In vitro genotoxicity studies with the read across substances did not indicating metabolism to more toxic compounds in vitro and probably also in vivo. Cytotoxic effects which were observed were unaltered or reduced in the presence of metabolic S9-mix.
Phosphoric acid alcyl esters are supposed to be metabolized by esterases taking part in the mammalian phase I metabolism. It is further assumed that hydrolysation of the phosphoric acid alkyl esters by those esterases is independent from the constitution of the alkyl chain (alcoholic compound). Therefore, no mechanistic differences in the metabolism of the target and the source substances are to be expected. A complete hydrolysation of the phosphate esters present in the target substance is expected, resulting in phosphate and the respective alcohols. Phosphate may enter the bloodstream and can be eliminated via urine. The alcoholic part of the former phosphate ester is further metabolized in the liver. The alcohols are oxidized to the corresponding carboxylic acids and their C2 units are afterwards eliminated stepwise via mitochondrial β-oxidation.

Conclusions:

Based on physicochemical characteristics absorption of the test substance by the oral route is expected. However, no signs of systemic toxicity were observed in an acute oral toxicity study. Bioaccumulation of the substance is not assumed to occur. A complete hydrolysation of the phosphate esters is expected. The phosphates are via urine.

Executive summary:

Based on physicochemical characteristics absorption of the test substance by the oral route is expected. However, no signs of systemic toxicity were observed in an acute oral toxicity study as well as in oral repeated dose toxicity studies with read-across substances. The substance has a low volatility (low vapour pressure) and is not likely to become available as a vapour. Dermal uptake is expected to be low. No bioaccumulation of the substance is expected. It is assumed that after oral uptake the test substance will be metabolised in the GI tract. A complete hydrolysation of the phosphate esters is expected, resulting in phosphate and the respective alcohols.The phosphates are excreted via urine.

Description of key information

Based on physicochemical characteristics absorption of the test substance by the oral route is expected. However, no signs of systemic toxicity were observed in an acute oral toxicity study and oral repeated dose toxicity studies with read-across substances. The substance has a low volatility (low vapour pressure) and is not likely to become available as a vapour. Dermal uptake is expected to be low. No bioaccumulation of the substance is expected. It is assumed that after oral uptake the test substance will be metabolised in the GI tract. A complete hydrolysation of the phosphate esters is expected, resulting in phosphate and the respective alcohol/s.The phosphates are excreted via urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Absorption

Generally, the smaller the molecule the more easily it may be taken up via oral route. Oral absorption is favoured for substances with a molecular weight below 500 g/mol. Substances with molecular weights above 1000 g/mol do not favour absorption. The molecular weight of the substance ranges from 304 to 641 g/mol. Therefore based on molecular weight the substances may be absorbed after oral intake. The water solubility / critical micelle concentration (55 mg/L) and the moderate log Pow-values (0.51) further support oral absorption. However, the available study data on acute oral toxicity (read across to C12 and C18-ester) do not support this assumption, as no deaths occurred and apart from piloerection no signs of (test item-related) systemic toxicity were noted up to the test concentration of 2000 mg/kg bw. Furthermore, no systemic effects were revealed in the OECD 422 study conducted with the read across-substance phosphoric acid, dodecyl ester, sodium salt up to the highest test concentration of 1000 mg/kg bw. The NOEL for male animals of 125 mg/kg bw/d and a NOEL for female animals of 62.5 mg/kg bw/d was determined based on local effects on the gastrointestinal mucosa due to the irritative nature of the test item. In a study according to OECD 421 conducted with the read across-substance Hexadecyl dihydrogen phosphate, there were also no signs of systemic toxicity observed up to the highest concentration of 1000 mg/kg bw.

The substance has a low volatility (low vapour pressure) and is not likely to become available as a vapour.

As the substance has a local effect on skin, damage to skin surface may enhance penetration. But, due to the water solubility of 55 mg/L absorption is anticipated to be low. Besides that, the log Pow of 0.51 indicates that penetration into the stratum corneum is limited. By using Dermwin v2.02 the Kp value of one read across-substances (Phosphoric acid, dodecyl ester, potassium salt, CAS 39322-78-6) was estimated to be 0.00203 cm/h, indicating that dermal uptake is low.

Distribution

In general, the smaller the molecule the wider the distribution. The target and source substances show a molecular weight between 210 and 641 g/mol. Available study data with the substance itself or the read across-substances do not reveal target organs/tissues that could be taken as proof of distribution into a specific compartment or organ. It is assumed that after oral uptake the test substance will be metabolised in the GI tract and excreted. The log Pow value of 0.51 does further not imply a bioconcentration potential of the substance. The available study data revealed no indications of the substance to cross the blood-brain barrier.

Metabolism

In vitro genotoxicity studies with the read across substances did not indicating metabolism to more toxic compounds in vitro and probably also in vivo. Cytotoxic effects which were observed were unaltered or reduced in the presence of metabolic S9-mix.

Phosphoric acid alkyl esters are supposed to be metabolized by esterases taking part in the mammalian phase I metabolism. It is further assumed that hydrolysation of the phosphoric acid alkyl esters by those esterases is independent from the constitution of the alkyl chain (alcoholic compound). Therefore, no mechanistic differences in the metabolism of the target and the source substances are to be expected. A complete hydrolysation of the phosphate esters present in the target substance is expected, resulting in phosphate and the respective alcohols. Phosphate may enter the bloodstream and can be eliminated via urine. The alcoholic part of the former phosphate ester is further metabolized in the liver. The alcohols are oxidized to the corresponding carboxylic acids and their C2 units are afterwards eliminated stepwise via mitochondrial β-oxidation.

Excretion

The remaining phosphates are excreted via urine.