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

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: expert statement

Adequacy of study:

key study

Study period:

SEP 2014

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Theoretical assessment taking all currrently available relevant information into account, based on the REACH Guidance: Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c Endpoint specific guidance. Since this is a theoretical assessment, the Klimisch value cannot be 1.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2014

Report date:

2014

Materials and methods

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

451-060-3

EC Name:

-

Cas Number:

122886-55-9

Molecular formula:

Hill formula: C31H48N4O2 CAS formula: C31H48N4O2

IUPAC Name:

N,N’’-(methylenedi-4,1-phenylene)bis(N’-octylurea)

Constituent 2

Reference substance name:

N-{4-[(4-{[(octadecylamino)carbonyl]amino}phenyl)methyl]phenyl}-N’-octylurea

Cas Number:

117328-86-6

Molecular formula:

Hill formula: C41H68N4O2 CAS formula: C41H68N4O2

IUPAC Name:

N-{4-[(4-{[(octadecylamino)carbonyl]amino}phenyl)methyl]phenyl}-N’-octylurea

Constituent 3

Reference substance name:

3,3'-dioctadecyl-1,1'-methylenebis(4,1-phenylene)diurea

EC Number:

406-690-3

EC Name:

3,3'-dioctadecyl-1,1'-methylenebis(4,1-phenylene)diurea

Cas Number:

43136-14-7

Molecular formula:

Hill formula: C51H88N4O2 CAS formula: C51H88N4O2

IUPAC Name:

N,N’’-(methylenedi-4,1-phenylene)bis(N’-octadecylurea)

Test material form:

solid: particulate/powder

Details on test material:

- Name of test material (as cited in study report): KY-EU
- Appearance: white powder
- Storage condition of test material: in darkness at room temperature

Results and discussion

Main ADME results

Type:

absorption

Results:

For risk assessment purposes, 10% is used for oral, dermal and inhalation absorption

Any other information on results incl. tables

A toxicant can enter the body after oral exposure, by inhalation or after dermal exposure. To

determine the absorption rate, the different routes are assessed individually. In general, a

compound needs to be dissolved before it can be taken up from the gastrointestinal tract after

oral exposure. KY-EU has a low water solubility (4.38 μg/L) and therefore uptake by

passive diffusion is expected to be limited. KY-EU is a reaction mass with multiple constituents.

Based on its three main components, its weighted average molecular weight is 632.8 g/mole. This high molecular weight does not favor absorption. KY-EU has a high partition coefficient (log Pow ≥6 at 26°C), which indicates that the compound is very hydrophobic. This

characteristic allows micellular solubilisation by bile salts in the gastro-intestinal tract which

enables the substance to some extent to cross lipid biomembranes.

For risk assessment purposes oral absorption of KY-EU is set at 10%, based on its high

log Pow, low water solubility and its high molecular weight. The results of the toxicity studies do

not provide reasons to deviate from this proposed oral absorption factor.

Once absorbed, wide distribution of the test substance throughout the body is not expected

based on its low water solubility and its high molecular weight. Based on its high partition

coefficient (log Pow ≥6 at 26°C), it can generally be assumed that KY-EU will distribute into cells

and accumulate in adipose tissue. However, for highly hydrophobic substances, experimental

data demonstrate that both the bioconcentration factor and the bioaccumulation factor tend to

decrease with increasing log Pow (above 6 and above 7.5 resp.).Therefore, based on these

data, distribution and accumulation is expected to be low.

Excretion of KY-EU and its metabolites will occur via the bile (high molecular weight) or the

urine (low molecular weight; 2). The low vapour pressure of the substance (<0.00026 Pa at

25°C) indicates that KY-EU is not expected to evaporate and reach the nasopharyncheal

region or subsequently the tracheo/bronchial/pulmonary region via inhalation. Furthermore, it

has been shown that all KY-EU particles were >17 μm and approximately 92% of all particles

were >100 μm. This indicates that the presence of inhalable and/ or respirable particles will be

limited. If any particles reach the respiratory tract, particles above 50 μm are expected not to

penetrate the lower regions. If KY-EU reaches the tracheobronchial region, it is not likely to

dissolve within the mucus lining of the respiratory tract due to its low water solubility. However, if it

dissolves into the mucus lining, based on its high log Pow, it is likely that micellular solubilisation

will occur which will enable uptake of the substance by crossing of biomembranes. Based on

the above data, for risk assessment purposes the inhalation absorption of KY-EU is set at 10%.

KY-EU is a solid, thus when it comes in contact with the skin, absorption is not very likely. Due

to its very low water solubility, KY-EU will only dissolve to a limited extent in body fluids.

Furthermore, the first layer of the skin, the stratum corneum, forms a barrier for hydrophilic

compounds. KY-EU has a log Pow ≥6, suggesting that the substance is not hydrophilic and can be taken up in the stratum corneum. However, due to its low water solubility, the transfer

between the stratum corneum and the epidermis will be limited. According to the criteria given in

the REACH Guidance, 10% dermal absorption will be considered in case MW >500 and log

Pow <-1 or >4, otherwise 100% dermal absorption should be used. As the physical/chemical

properties of KY-EU meet the criteria for limited dermal absorption (MW = 632.8 g/mole (based on the

weighted average MWs of the main components) and log Pow ≥6), for risk assessment

purposes dermal absorption is set at 10%. The results of the toxicity studies do not provide

reasons to deviate from this proposed dermal absorption factor.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
For risk assessment purposes, 10% is used for oral, dermal and inhalation absorption.