2,4(1H,3H)-Pyrimidinedione, 1-(3,5-di-O-acetyl-2-deoxy-.beta.-L-erythro-pentofuranosyl)-5-methyl-

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2001 - 2019

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2019

Report date:

2019

Materials and methods

Objective of study:

absorption

distribution

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

This theoretical assessment was prepared, taking all currently available relevant information
into account, based on the REACH Guidance: Guidance on Information Requirements and
Chemical Safety Assessment, Chapter R.7c Endpoint specific guidance.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

[(2S,3R,5S)-3-acetoxy-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl]methyl acetate

EC Number:

610-122-1

Cas Number:

433733-94-9

Molecular formula:

C14H18N2O7

IUPAC Name:

[(2S,3R,5S)-3-acetoxy-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl]methyl acetate

Radiolabelling:

no

Administration / exposure

Details on study design:

This theoretical assessment was prepared, taking all currently available relevant information
into account, based on the REACH Guidance: Guidance on Information Requirements and
Chemical Safety Assessment, Chapter R.7c Endpoint specific guidance.

Results and discussion

Preliminary studies:

A substance can enter the body via the gastrointestinal tract, the lungs, or the skin, depending
on the exposure route. To determine the rate of absorption adequately, the different exposure
routes are assessed individually.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

After oral administration, in general, a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract (1). Diacetyl Thymidine (LDT600-C3) dissolves well in water (12.9 g/L at 20°C), therefore passive diffusion (passage of small water-soluble molecules through aqueous pores or carriage of such molecules across membranes with the bulk passage of water) is expected. The molecular weight of Diacetyl Thymidine (LDT600-C3) (326.3) will not hamper fast absorption, as smaller molecules with a molecular weight below 500 are taken up easily. Similarly, the lipophilicity of the substance is moderate (resulting in a log Pow of 1), which allows penetration through lipid membranes by passive diffusion. Diacetyl Thymidine (LDT600-C3) does not have ionisable groups, implying that potential uptake will not be hampered by presence of charged groups. Finally, the hydrolysis data indicate that the substance is stable at lower pH at body temperature, therefore rapid breakdown in the gastro-intestinal tract is not expected.
Taken together, absorption of Diacetyl Thymidine (LDT600-C3) after oral exposure is to be expected due to its moderate lipophilicity and good water solubility. Furthermore, its size and the fact that the substance is not ionisable do not indicate hampering of uptake. For risk assessment purposes oral absorption of Diacetyl Thymidine (LDT600-C3) is therefore set at 100% The oral toxicity data do not provide reason to deviate from the proposed oral absorption factor.
Diacetyl Thymidine (LDT600-C3) has a very low vapour pressure (2.12*10-8 Pa at 20°C) and no boiling point. This implies that exposure via inhalation of vapour is not likely to occur. On the other hand, Diacetyl Thymidine (LDT600-C3) particles are small (D10 = 86.83 μm, D50 = 260.5 μm and D90 = 506.6 μm). In general, particles with aerodynamic diameters below 100 μm have the potential to be inhaled, which will be the case for a minor part of the substance. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm can enter the alveolar region of the respiratory tract (2). This indicates that during exposure to Diacetyl Thymidine (LDT600-C3) by inhalation some particles may reach both the nasopharyncheal region and the tracheo/bronchial/pulmonary region. Once Diacetyl Thymidine (LDT600-C3) reaches the lung tissue, it will dissolve within the mucus lining of the respiratory tract and will be taken up. Related to the very low vapour pressure and based on the fact that the inhalable part is expected to be less than 50% of the substance, for risk assessment purposes the inhalation absorption of Diacetyl Thymidine (LDT600-C3) is set at 50%.
Diacetyl Thymidine (LDT600-C3) is a powder, and in this state uptake through skin is expected to be very limited. In presence of fluid (e.g. skin moisture), it will dissolve which allows adsorption into the skin. The first layer of the skin, the stratum corneum, is a barrier for hydrophilic compounds. As Diacetyl Thymidine (LDT600-C3) is of moderate lipophilicity, some penetration by passive diffusion through lipid layers is to be expected. Furthermore, Diacetyl Thymidine (LDT600-C3) has a molecular weight below 500, which will not hamper fast absorption. The substance is expected not to be ionized, implying adsorption will not be negatively influenced by for example binding to skin components.
According to the criteria given in the REACH Guidance (2), 10% dermal absorption will be considered in case MW >500 and log Pow <-1 or >4, otherwise 100% dermal absorption should be used. With regard to both parameters, Diacetyl Thymidine (LDT600-C3) does not fulfill the criteria (MW > 500). Based on these considerations, for risk assessment purposes dermal absorption is set at 100%.

Details on distribution in tissues:

Once absorbed, wide distribution of the test substance throughout the body is expected based on its molecular weight (MW = 326.3) and water solubility (12.9 g/L at 20°C). Furthermore, related to the moderate lipophilicity of Diacetyl Thymidine (LDT600-C3) (log Pow = 1), the substance is not expected to accumulate in adipose tissue. Absorbed Diacetyl Thymidine (LDT600-C3) is most likely excreted via urine and/ or bile. In conclusion, Diacetyl Thymidine (LDT600-C3) is not expected to bio-accumulate significantly in the body upon exposure.

Metabolite characterisation studies

Metabolites identified:

not specified

Applicant's summary and conclusion

Conclusions:

A toxicokinetic assessment for Diacetyl Thymidine (LDT600-C3) was performed. Based on the physical/chemical properties of the substance, absorption factors for this substance are derived to be 100% (oral), 50% (inhalation) and 100% (dermal) for risk assessment purposes.
The bioaccumulation potential is expected to be low.