Phosphoric acid, butyl ester, sodium salt

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:

According to ECHA Guidance R.7c, the smaller the molecule the more easily it may be taken up via oral route. Generally, oral absorption is favoured for molecular weights below 500 g/mol. Molecular weights above 1000 g/mol do not favour absorption. Furthermore, water soluble substances will readily dissolve in the gastrointestinal fluids. Moderate log Pow values (between -1 and 4) are favourable for absorption by passive diffusion. No water solubility had been determined for Afilan AKT liq as it is a surfactant, but based on the molecular weights of the constituents (70 to 600 g/mol) and the log Pow of 1.52 oral absorption may be possible, although the acute oral toxicity studies with the substance itself revealed no clinical signs or mortality. The read-across substance dibutyl hydrogen phosphate was also shown to not cause mortality in the acute oral toxicity study in rats, but some signs of systemic suppression were noted after administration, indicating that oral absorption has occurred. In a repeated-dose toxicity study with the read-across substance clinical signs, morality as well as histopathological findings were observed demonstrating that oral absorption has occurred.
Based on the molecule size and log Pow value dermal absorption may be possible but no experimental data are available. The substance is classified as irritant to skin, indicating that dermal uptake might be enhanced through local damage to the skin.
As the substance has a low volatility (low vapour pressure of 0.000015 Pa at 20 °C), it is not available for inhalation as a vapour.

Details on distribution in tissues:

In general, the smaller the molecule, the wider the distribution. Lipophilic molecules (log Pow > 0) are likely to distribute into cells and the intracellular concentration may be higher than the extracellular concentration. The available experimental data did not indicate that the substance reaches the central nervous system, as no CNS effects were noted. The oral repeated dose toxicity study conducted with the read-across substance dibutyl hydrogen phosphate revealed some effects in the liver (increase in liver weight and size in some animals), and besides that local effects (damage to mucosa) were found in the gastric mucosa and bladder.

Details on excretion:

Large amounts of the substance having passed the GI will be excreted in their unchanged form. Besides that, metabolites such as carboxylated and hydroxylated molecules are formed. Excretion takes place via urine.

Details on metabolites:

In in vitro genotoxicity studies no remarkable differences in regard to genotoxicity and cytotoxicity in the presence or absence of metabolic S9-mix could be detected, therefore not indicating metabolism to more toxic compounds in vitro and probably also in vivo. This is confirmed by a study investigating the metabolism of the read-across substance dibutyl hydrogen phosphate by rat liver homogenate in vitro: As a result, dibutyl hydrogen phosphate was not found to be metabolised. Furthermore, a study was conducted in rats examining the metabolism of the read-across substance butyl dihydrogen phosphate after intraperitoneal application. A large amount of the applied test substance was found unchanged in the urine (47.6 %). The urine also contained metabolites with carboxylated or hydroxylated butyl side chains and also butyl dihydrogen phosphate. The same is anticipated for the target substance constituents, as the same functional groups are present in the molecules.

Conclusions:

Based on physicochemical characteristics absorption of the substance by the oral route is expected. This assumption was supported by an oral toxicity study with the read-across substance dibutyl hydrogen phosphate, revealing clinical signs, morality and/or histopathological findings. Dermal absorption may be possible based on physicochemical properties but no experimental data are available. As the substance has a low vapour pressure, it is not available for inhalation as a vapour. The repeated dose oral toxicity study with the read-across substance dibutyl hydrogen phosphate indicated that the substance is distributed to liver, gastric mucosa as well as bladder. Excretion of the substance itself and its metabolites occurs via urine.

Executive summary:

Based on physicochemical characteristics absorption of the test substance by the oral route is expected.This assumption was supported by an acute oral toxicity study and a repeated dose oral toxicity study with theread-across substance dibutyl hydrogen phosphate, revealing some signs of systemic suppression (acute oral toxicity study) and clinical signs, morality and/or histopathological findings (repeated dose oral toxicity study). Dermal absorption may be possible based onphysicochemical propertiesbut no experimental data are available. As the substance has a low vapour pressure, it is not available for inhalation as a vapour. The repeated dose oral toxicity studywith theread-across substance dibutyl hydrogen phosphate indicated that the substance is distributed to liver, gastric mucosa as well as bladder. Large amounts of the substance having passed the GI will be excreted in its unchanged form. Besides that, metabolites such as carboxylated and hydroxylated molecules are formed. Excretion of the substance itself and its metabolites takes place via urine.

Description of key information

Based on physicochemical characteristics absorption of the substance by the oral route is expected.This assumption was supported by an oral toxicity study with theread-across substance dibutyl hydrogen phosphate, revealing clinical signs, morality and/or histopathological findings. Dermal absorption may be possible based onphysicochemical propertiesbut no experimental data are available. As the substance has a low vapour pressure, it is not available for inhalation as a vapour. The repeated dose oral toxicity studywith theread-across substance dibutyl hydrogen phosphate indicated that the substance is distributed to liver, gastric mucosa as well as bladder. Excretion of the substance itself and its metabolites occurs via urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Absorption:

According to ECHA Guidance R.7c, the smaller the molecule the more easily it may be taken up via oral route.Generally, oral absorption is favoured for molecular weightsbelow 500 g/mol. Molecular weights above 1000 g/mol do not favour absorption. Furthermore, water soluble substances will readily dissolve in the gastrointestinal fluids. Moderate log Pow values (between -1 and 4) are favourable for absorption by passive diffusion. No water solubility had been determined for Afilan AKT liq as it is a surfactant, but based on the molecular weights of the constituents (70 to 600 g/mol) and the log Pow of 1.52 oral absorption may be possible, although the acute oral toxicity studies with the substance itself revealed no clinical signs or mortality. The read-across substance dibutyl hydrogen phosphate was also shown to not cause mortality in the acute oral toxicity study in rats, but some signs of systemic suppression were noted after administration, indicating that oral absorption has occurred. In a repeated-dose toxicity study with the read-across substance clinical signs, morality as well as histopathological findings were observed demonstrating that oral absorption has occurred.

Based on the molecule size and log Pow value dermal absorption may be possible but no experimental data are available. The substance is classified as irritant to skin, indicating that dermal uptake might be enhanced through local damage to the skin.

As the substance has a low volatility (low vapour pressure of 0.000015 Pa at 20 °C), it is not available for inhalation as a vapour.

Distribution:

In general, the smaller the molecule, the wider the distribution. Lipophilic molecules (log Pow > 0) are likely to distribute into cells and the intracellular concentration may be higher than the extracellular concentration. The available experimental data did not indicate that the substance reaches the central nervous system, as no CNS effects were noted. The oral repeated dose toxicity study conducted with the read-across substance dibutyl hydrogen phosphate revealed some effects in the liver (increase in liver weight and size in some animals), and besides that local effects (damage to mucosa) were found in the gastric mucosa and bladder.

Metabolism:

In in vitro genotoxicity studies no remarkable differences in regard to genotoxicity and cytotoxicity in the presence or absence of metabolic S9-mix could be detected, therefore not indicating metabolism to more toxic compounds in vitro and probably also in vivo. This is confirmed by a study investigating the metabolism of the read-across substance dibutyl hydrogen phosphate by rat liver homogenate in vitro: As a result, dibutyl hydrogen phosphate was not found to be metabolised. Furthermore, a study was conducted in rats examining the metabolism of the read-across substance butyl dihydrogen phosphate after intraperitoneal application. A large amount of the applied test substance was found unchanged in the urine (47.6 %). The urine also contained metabolites with carboxylated or hydroxylated butyl side chains and also butyl dihydrogen phosphate.The same is anticipated for the target substance constituents, as the same functional groups are present in the molecules.

 

Excretion:

Large amounts of the substance having passed the GI will be excreted in their unchanged form. Besides that, metabolites such as carboxylated and hydroxylated molecules are formed. Excretion takes place via urine.