Reaction mass of lauric acid, compound with morpholine (1:1) and 2-ethylhexyl dihydrogen phosphate, compound with morpholine (1:2) and bis(2-ethylhexyl) hydrogen phosphate, compound with morpholine (1:1)

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert Statement

Adequacy of study:

key study

Study period:

15 May 2918

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert Statement, no study available

Qualifier:

no guideline required

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

Details on absorption:

Absorption is a property of a substance to diffuse across biological membranes. Generally, oral absorption is favored for molecular weights below 500 g/mol and log Pow values between -1 and 4. In the GI tract absorption of small water-soluble molecules (molecular weight up to around 200 g/mol) occurs through aqueous pores or carriage of such molecules across membranes with the bulk passage of water. Therefore, it can be considered as likely that Reaction mass of lauric acid, compound with morpholine (1:1) and 2-ethylhexyl dihydrogen phosphate, compound with morpholine (1:2) and bis(2-ethylhexyl) hydrogen phosphate, compound with morpholine (1:1) becomes bioavailable following the oral route, as indicated by its physicochemical properties. This assumption is supported by the results of acute oral and repeated dose oral toxicity studies where clinical signs and mortality were observed indicating systemic bioavailability.

Absorption via the respiratory route also depends on physico-chemical properties like vapour pressure, log Pow and water solubility. In general, highly volatile substances are those with a vapour pressure greater than 25 kPa or boiling point below 50°C. Substances with log Pow values between -1 and 4 are favored for absorption directly across the respiratory tract epithelium by passive diffusion. Due to its low vapour pressure of 0.0159 Pa at 20°C and 0.0216 Pa at 25°C Reaction mass of lauric acid, compound with morpholine (1:1) and 2-ethylhexyl dihydrogen phosphate, compound with morpholine (1:2) and bis(2-ethylhexyl) hydrogen phosphate, compound with morpholine (1:1) is unlikely to be available as a vapour and exposure and uptake via inhalation is considered as negligible. Furthermore, the substance is a waxy liquid and no production of dust is expected.

In general, dermal absorption is favored by small molecular weights and high water solubility of the substance. Log Pow values between 1 and 4 favor dermal absorption, particularly if water solubility is high. However, if water solubility is above 10 g/L and the log Pow value below 0 the substance may be too hydrophilic to cross the lipid rich stratum corneum and dermal uptake will be low. Therefore, for Reaction mass of lauric acid, compound with morpholine (1:1) and 2-ethylhexyl dihydrogen phosphate, compound with morpholine (1:2) and bis(2-ethylhexyl) hydrogen phosphate, compound with morpholine (1:1) low dermal absorption is predicted because of its high water solubility and log Pow value of < 0.3. In an acute dermal toxicity study no systemic toxicity was noted up to 2000 mg/kg bw indicating low dermal bioavailability. As the substance is identified as skin sensitizer, some dermal uptake of the applied substance must have been occurred probably enhanced via the damaged skin surface as a result of irritant reactions.

Details on distribution in tissues:

In general, the smaller the molecule the broader is its distribution. Small water-soluble molecules will diffuse through aqueous channels and pores in the membranes. After being absorbed into the body, Reaction mass of lauric acid, compound with morpholine (1:1) and 2-ethylhexyl dihydrogen phosphate, compound with morpholine (1:2) and bis(2-ethylhexyl) hydrogen phosphate, compound with morpholine (1:1) is expected to distribute through-out the body water. In the acute and repeated dose toxicity study described above various clinical signs in different organs were observed indicating a broad distribution of the substance. Due to its low log Pow the test item is unlikely to bioaccumulate in tissue, and there are no other physicochemical properties indicating bio-accumulating properties.

Details on excretion:

In general, urinary excretion in favored by low molecular weight (below 300 g/mol in the rat) good water solubility, and ionization of the molecule. In rats for organic cations with a molecular weight above 300 it is likely to be excreted via bile and in the faeces.
Therefore, Reaction mass of lauric acid, compound with morpholine (1:1) and 2-ethylhexyl dihydrogen phosphate, compound with morpholine (1:2) and bis(2-ethylhexyl) hydrogen phosphate, compound with morpholine (1:1) and its metabolites are expected to be excreted mainly via urine but also via faeces.

Details on metabolites:

It is described in the scientific literature that morpholine, a component of Reaction mass of lauric acid, compound with morpholine (1:1) and 2-ethylhexyl dihydrogen phosphate, compound with morpholine (1:2) and bis(2-ethylhexyl) hydrogen phosphate, compound with morpholine (1:1) can be metabolized via different routes. The major routes involve various oxidative processes, including N-oxidation and dealkylation followed by deamination and other enzyme-catalyzed reactions. Most of the administered dose is excreted unchanged via urine. For lauric acid, another component of the target substance, degradation via beta- oxidation to carboxylic acids is expected followed by generation to CO2 and H2O as final products. Furthermore, it is reported that bis(2-ethylhexyl) dihydrogen phosphate, another compound of the substance is metabolized after oral dietary administration to rats to form 2-ethylhexanol, which was showed to induce xenobiotic-metabolizing enzymes. From in vitro genotoxicity studies with the target substance no remarkable differences in regard to genotoxicity and cytotoxicity in the presence or absence of metabolic S9 Mix could be detected, which might indicate that no metabolic activation of the substance occurs in vitro and probably also in vivo.

Conclusions:

Based on physico-chemical properties, oral absorption and distribution through-out the body is expected. Dermal absorption is expected to be low. These assumptions are supported by the results of single and repeated-dose toxicity studies in vivo. Absorption via the inhalation route is, due to physico-chemical properties of the substance, not expected. Bioaccumulation of Reaction mass of lauric acid, compound with morpholine (1:1) and 2-ethylhexyl dihydrogen phosphate, compound with morpholine (1:2) and bis(2-ethylhexyl) hydrogen phosphate, compound with morpholine (1:1) is not expected after continuous exposure. For the single components of this multi-constituent substance metabolisation via various enzyme-catalyzed routes is expected. The test substance and its metabolites are expected to be predominantly excreted via urine and to a lower extent via faeces.

Description of key information

Based on physico-chemical properties, oral absorption and distribution through-out the body is expected. Dermal absorption is expected to be low.These assumptions are supported by the results of single and repeated-dose toxicity studiesin vivo.Absorption via the inhalation route is, due to physico-chemical properties of the substance, not expected. Bioaccumulation of Reaction mass of lauric acid, compound with morpholine (1:1) and 2-ethylhexyl dihydrogen phosphate, compound with morpholine (1:2) and bis(2-ethylhexyl) hydrogen phosphate, compound with morpholine (1:1) is not expected after continuous exposure. For the single components of this multi-constituent substance metabolisation via various enzyme-catalyzed routes is expected. The test substance and its metabolites are expected to be predominantly excreted via urine and to a lower extent via faeces.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Reaction mass of lauric acid, compound with morpholine (1:1) and 2-ethylhexyl dihydrogen phosphate, compound with morpholine (1:2) and bis(2-ethylhexyl) hydrogen phosphate, compound with morpholine (1:1) is a waxy liquid at ambient conditions with a molecular weight range from ≥ 210 ≤ 402 g/mol and a density of 1.0306 g/cm3. The test item is miscible with water at any ratio at ambient temperature. The log Pow of the multi-constituent substance was determined to be < 0.3. The vapour pressure is0.0159 Pa at 20°C and 0.0216 Pa at 25°C, respectively. The substance has a melting range from-0.6 °C to 19.7 °C and the boiling point was determined to be 150.1°C.

Absorption

Absorption is a property of a substance to diffuse across biological membranes.Generally, oral absorption is favored for molecular weights below 500 g/mol andlog Pow values between -1 and 4.In the GI tract absorption of small water-soluble molecules(molecular weight up to around 200 g/mol) occurs through aqueous pores or carriage of such molecules across membranes with the bulk passage of water. Therefore, it can be considered as likely that Reaction mass of lauric acid, compound with morpholine (1:1) and 2-ethylhexyl dihydrogen phosphate, compound with morpholine (1:2) and bis(2-ethylhexyl) hydrogen phosphate, compound with morpholine (1:1) becomes bioavailable following the oral route, as indicated by its physicochemical properties. This assumption is supported by the results of acute oral and repeated dose oral toxicity studies where clinical signs and mortality were observed indicating systemic bioavailability.

Absorption via the respiratory route also depends on physico-chemical properties like vapour pressure, log Pow and water solubility. In general, highly volatile substances are those with a vapour pressure greater than 25 kPa or boiling point below 50°C. Substances with log Pow values between -1 and 4 are favored for absorption directly across the respiratory tract epithelium by passive diffusion. Due to its low vapour pressure of 0.0159 Pa at 20°C and 0.0216 Pa at 25°C Reaction mass of lauric acid, compound with morpholine (1:1) and 2-ethylhexyl dihydrogen phosphate, compound with morpholine (1:2) and bis(2-ethylhexyl) hydrogen phosphate, compound with morpholine (1:1) is unlikely to be available as a vapour and exposure and uptake via inhalation is considered as negligible. Furthermore, the substance is a waxy liquid and no production of dust is expected.

In general, dermal absorption is favored by small molecular weights and high water solubility of the substance. Log Pow values between 1 and 4 favor dermal absorption, particularly if water solubility is high. However, if water solubility is above 10 g/L and the log Pow value below 0 the substance may be too hydrophilic to cross the lipid rich stratum corneum and dermal uptake will be low. Therefore, for Reaction mass of lauric acid, compound with morpholine (1:1) and 2-ethylhexyl dihydrogen phosphate, compound with morpholine (1:2) and bis(2-ethylhexyl) hydrogen phosphate, compound with morpholine (1:1) low dermal absorption is predicted because of its high water solubility and log Pow value of < 0.3. In an acute dermal toxicity studyno systemic toxicity was noted up to 2000 mg/kg bw indicating low dermal bioavailability. As the substance is identified as skin sensitizer, some dermal uptake of the applied substance must have been occurred probably enhanced via the damaged skin surface as a result of irritant reactions.

Distribution

In general, the smaller the molecule the broader is its distribution. Small water-soluble molecules will diffuse through aqueous channels and pores in the membranes.After being absorbed into the body, Reaction mass of lauric acid, compound with morpholine (1:1) and 2-ethylhexyl dihydrogen phosphate, compound with morpholine (1:2) and bis(2-ethylhexyl) hydrogen phosphate, compound with morpholine (1:1) is expected to distribute through-out the body water. In the acute and repeated dose toxicity study described above variousclinical signs in different organs were observed indicating a broad distribution of the substance.Due to its low log Pow the test item is unlikely to bioaccumulate in tissue,and there are no other physicochemical properties indicating bio-accumulating properties.

Metabolism

It is described in the scientific literature that morpholine, a component of Reaction mass of lauric acid, compound with morpholine (1:1) and 2-ethylhexyl dihydrogen phosphate, compound with morpholine (1:2) and bis(2-ethylhexyl) hydrogen phosphate, compound with morpholine (1:1) can be metabolized via different routes. The major routes involve various oxidative processes, including N-oxidation and dealkylation followed by deamination and other enzyme-catalyzed reactions. Most of the administered dose is excreted unchanged via urine. For lauric acid, another component of the target substance, degradation via beta- oxidation to carboxylic acids is expected followed by generation to CO2 and H2O as final products. Furthermore, it is reported that bis(2-ethylhexyl) dihydrogen phosphate, another compound of the substance is metabolized after oral dietary administration to rats to form 2-ethylhexanol, which was showed to induce xenobiotic-metabolizing enzymes. From in vitro genotoxicity studies with the target substance no remarkable differences in regard to genotoxicity and cytotoxicity in the presence or absence of metabolic S9 Mix could be detected, which might indicate that no metabolic activation of the substance occurs in vitro and probably also in vivo.

Excretion

In general, urinary excretion in favored by low molecular weight (below 300 g/mol in the rat) good water solubility, and ionization of the molecule. In rats for organic cations with a molecular weight above 300 it is likely to be excreted via bile and in the faeces.

Therefore, Reaction mass of lauric acid, compound with morpholine (1:1) and 2-ethylhexyl dihydrogen phosphate, compound with morpholine (1:2) and bis(2-ethylhexyl) hydrogen phosphate, compound with morpholine (1:1) and its metabolites are expected to be excreted mainly via urine but also via faeces.