N,N''-(methylenedi-4,1-phenylene)bis[N'-octylurea]

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

Toxicokinetic assessment of the substance based on the available data

Type of information:

other: expert statement

Adequacy of study:

key study

Study period:

Not applicable

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: since this is a theoretical assessment, the Klimisch value cannot be 1.

Objective of study:

other: Toxicokinetic assessment of the substance based on the available data

Qualifier:

according to guideline

Guideline:

other: Guidance for the implementation of REACH. Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. European Chemical Agency, Version 6.0

Version / remarks:

November 2016

Deviations:

no

GLP compliance:

no

Type:

absorption

Results:

The absorption factors for risk assessment purposes are derived to be 10% (oral), 100% (inhalation) and 10% (dermal).

Toxicokinetic assessment

A toxicant can enter the body via the gastrointestinal tract, the lungs and the skin. In general, a compound needs to be dissolved before it can be taken up from the gastrointestinal tract after oral administration.

KY-UN has a very low water solubility of < 3.03 μg/L. This implies that the substance will only dissolve to a limited extend into the gastrointestinal fluids and consequently uptake via passive diffusion (passage of small water-soluble molecules through aqueous pores or carriage across membranes with the bulk passage of water) will be limited. In addition, the high molecular weight (508.74) is also not favorable for this process. KY-UN has a high partition coefficient, therefore this substance will dissolve in lipids and has the ability to cross epithelia by passive diffusion.

No data are available on the dissociation constant of KY-UN, therefore it is unclear in which state (ionized or not ionized) the substance will be present under physiological circumstances in the stomach or intestinal tracts. Since it is generally thought that ionized substances do not readily diffuse across biological membranes, the state of the substance might hamper uptake.

Considering all this data, oral absorption of KY-UN is considered to be limited due to its very low water solubility, its high molecular size, and its ability to dissolve in lipids. Therefore, for risk assessment purposes oral absorption of KY-UN is set at 10%. The oral toxicity data do not provide reasons to deviate from the proposed oral absorption factor.

The low vapour pressure (1.5E-12 Pa at 25°C) indicates that KY-UN is a substance with low volatility. Inhalation of vapour is therefore considered very limited. KY-UN is a powder, with a mean particle diameter (MMAD) of 72.6 μm, and with 50% of the particles having a diameter < 66.4 μm. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm can reach the alveolar region of the respiratory tract. Based on the size of the particles, a significant part of the particles are expected to be able to reach all parts of the lung upon inhalation. If the substance reaches these regions, KY-UN is not likely to dissolve in the mucus lining of the respiratory tract and to get absorbed significantly, due to the very low water solubility. Since KY-UN is able to dissolve in lipids, some uptake through respiratory epithelium is possible. In the absence of actual data on inhalation absorption, for risk assessment purposes the inhalation absorption of KY-UN will be set at 100%.

KY-UN is a powder and as its water solubility is very low, and consequently the ability to dissolve into the surface moisture of the skin followed by uptake and partition from the stratum corneum into the epidermis will be restricted. Its ability to dissolve in lipids will favour crossing of epidermal barriers, although its high molecular size is expected to hamper uptake through dermal epithelium. According to the guidance, a default value of 100% skin absorption is generally used unless molecular weight is above 500 and log Pow is outside the range [-1, 4]. Since KY-UN has a molecular weight of 508.74 and a log Pow >6, it does meet either criteria. Therefore, the dermal absorption of KY-UN for risk assessment purposes is set at 10%.

Once absorbed, distribution of the test substance throughout the body is expected to be limited based on its very low water solubility and high molecular weight. Absorbed KY-UN is expected to be excreted mainly via bile based on its very low water solubility and high molecular weight. Based on its partition coefficient, KY-UN is expected to accumulate in adipose tissue, and therefore bioaccumulation can be expected.

Conclusions:

A toxicokinetic assessment was performed based on the available data of KY-UN. Based on the physical/chemical properties of the substance, absorption factors for this substance are derived to be 10% (oral), 100% (inhalation) and 10% (dermal) for risk assessment purposes. The bioaccumulation potential is expected to be significant.

Description of key information

A toxicokinetic assessment was performed based on the available data of KY-UN. Based on the physical/chemical properties of the substance, absorption factors for this substance are derived to be 10% (oral), 100% (inhalation) and 10% (dermal) for risk assessment purposes. The bioaccumulation potential is expected to be significant.

Key value for chemical safety assessment

Bioaccumulation potential:

high bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

A toxicant can enter the body via the gastrointestinal tract, the lungs and the skin.

In general, a compound needs to be dissolved before it can be taken up from the gastrointestinal tract after oral administration. KY-UN has a very low water solubility of < 3.03 μg/L. This implies that the substance will only dissolve to a limited extend into the gastrointestinal fluids and consequently uptake via passive diffusion (passage of small water-soluble molecules through aqueous pores or carriage across membranes with the bulk passage of water) will be limited. In addition, the high molecular weight (508.74) is also not favorable for this process. KY-UN has a high partition coefficient, therefore this substance will dissolve in lipids and has the ability to cross epithelia by passive diffusion. No data are available on the dissociation constant of KY-UN, therefore it is unclear in which state (ionized or not ionized) the substance will be present under physiological circumstances in the stomach or intestinal tracts. Since it is generally thought that ionized substances do not readily diffuse across biological membranes, the state of the substance might hamper uptake. Considering all this data, oral absorption of KY-UN is considered to be limited due to its very low water solubility, its high molecular size, and its ability to dissolve in lipids. Therefore, for risk assessment purposes oral absorption of KY-UN is set at 10%. The oral toxicity data do not provide reasons to deviate from the proposed oral absorption factor.

The low vapour pressure (1.5E-12 Pa at 25°C) indicates that KY-UN is a substance with low volatility. Inhalation of vapour is therefore considered very limited. KY-UN is a powder, with a mean particle diameter (MMAD) of 72.6 μm, and with 50% of the particles having a diameter < 66.4 μm. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm can reach the alveolar region of the respiratory tract. Based on the size of the particles, a significant part of the particles are expected to be able to reach all parts of the lung upon inhalation. If the substance reaches these regions, KY-UN is not likely to dissolve in the mucus lining of the respiratory tract and to get absorbed significantly, due to the very low water solubility. Since KY-UN is able to dissolve in lipids, some uptake through respiratory epithelium is possible. In the absence of actual data on inhalation absorption, for risk assessment purposes the inhalation absorption of KY-UN will be set at 100%.

KY-UN is a powder and as its water solubility is very low, and consequently the ability to dissolve into the surface moisture of the skin followed by uptake and partition from the stratum corneum into the epidermis will be restricted. Its ability to dissolve in lipids will favour crossing of epidermal barriers, although its high molecular size is expected to hamper uptake through dermal epithelium. According to the guidance, a default value of 100% skin absorption is generally used unless molecular weight is above 500 and log Pow is outside the range [-1, 4]. Since KY-UN has a molecular weight of 508.74 and a log Pow >6, it does meet either criteria. Therefore, the dermal absorption of KY-UN for risk assessment purposes is set at 10%.

Once absorbed, distribution of the test substance throughout the body is expected to be limited based on its very low water solubility and high molecular weight. Absorbed KY-UN is expected to be excreted mainly via bile based on its very low water solubility and high molecular weight. Based on its partition coefficient, KY-UN is expected to accumulate in adipose tissue, and therefore bioaccumulation can be expected.