Reaction mass of 2-ethyl-2-[[3-(2-methylaziridin-1-yl)propionyl]methyl]propane-1,3-diyl bis(2-methylaziridine-1-propionate) and 2,2-bis({[3-(2-methylaziridin-1-yl)propanoyl]oxy}methyl)butyl 3-[2,2-bis({[3-(2-methylaziridin-1-yl)propanoyl]oxy}methyl)butoxy]propanoate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: expert statement

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP performed expert statement.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2012

Report date:

2012

Materials and methods

Objective of study:

absorption

Principles of method if other than guideline:

Expert statement based on the (physico-chemical) properties of the substance.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-({3-[2,2-bis({[3-(2-methylaziridin-1-yl)propanoyl]oxy}methyl)butoxy]-3-oxopropoxy}methyl)-2-({[3-(2-methylaziridin-1-yl)propanoyl]oxy}methyl)butyl 3-(2-methylaziridin-1-yl)propanoate; 2-ethyl-6-(2-methylaziridin-1-yl)-2-({[3-(2-methylaziridin-1-yl)propanoyl]oxy}methyl)-4-oxohexyl 3-(2-methylaziridin-1-yl)propanoate

EC Number:

939-180-9

Molecular formula:

Not relevant - Multiconstituent substance

IUPAC Name:

2-({3-[2,2-bis({[3-(2-methylaziridin-1-yl)propanoyl]oxy}methyl)butoxy]-3-oxopropoxy}methyl)-2-({[3-(2-methylaziridin-1-yl)propanoyl]oxy}methyl)butyl 3-(2-methylaziridin-1-yl)propanoate; 2-ethyl-6-(2-methylaziridin-1-yl)-2-({[3-(2-methylaziridin-1-yl)propanoyl]oxy}methyl)-4-oxohexyl 3-(2-methylaziridin-1-yl)propanoate

Results and discussion

Main ADME results

Type:

absorption

Results:

50% oral and dermal absorption and 100% inhalation absorption is used for risk assessment.

Any other information on results incl. tables

Although CX-100 hydrolyses rather fast ( t1/2 is 4.3 hours at pH 7 and 25°C ), the present toxicokinetic assessment is based on CX-100 and not on its degradation product(s), as available physical/chemical properties are confined to CX-100. The moderate molecular size (467.6) and relatively high water solubility (34.9 g/L) of CX-100 are favourable for absorption via the gastrointestinal tract. Furthermore, the moderate log Pow value (between -0.6 – 1.4 at pH 4 to 10) is favourable for absorption by passive diffusion (1). However, the presence of ionisable groups will impair the absorption, as ionized substances do not easily pass the gastrointestinal

wall. Based on these physical chemical properties, for risk assessment purposes the oral absorption is set at 50%.

Once absorbed, distribution of the substance throughout the body is expected based on its moderate molecular weight and relatively high water solubility. Absorbed CX-100 might undergo conjugation (3). The conjugates will either be excreted via the bile (high molecular weight compounds) or the urine (low molecular weight compounds).

The low vapour pressure and high boiling point indicate that CX-100 is not readily inhaled as a vapour. The moderate log Po/w (between -0.6 – 1.4 at pH 4 to 10) is favourable for crossing the alveolar and capillary membranes. The relatively high water solubility of the substance indicates that CX-100 will dissolve in the mucus lining of the respiratory tract and will either be retained

there or subsequently be absorbed through aqueous pores. Based on its physical and chemical properties, it is likely that the substance will be absorbed after inhalation via the lungs. For risk assessment purposes the inhalation absorption of the substance is therefore set at 100%.

CX-100 being a liquid has the potential to partition from the stratum corneum into the epidermis. The moderate water solubility (34.9 g/L) and the partition coefficient (log Po/w -0.6 to 1.4 at pH 4 to 10) are also favourable for dermal absorption. Based on the molecular weight (467.6) and the log Po/w, the criterion for 100% dermal absorption as given in the Guidance (2) (MW < 500

and/or -1 < log Po/w < 4) is met. Based on these physical chemical properties, for risk assessment purposes the dermal absorption is set at 100%. It is, however, generally accepted that dermal absorption is lower compared to oral absorption. The 100% dermal absorption derived from the physical/chemical properties of the substance should therefore be considered as unrealistic worst case assumption. For risk assessment purposes a lower dermal absorption value of 50% is considered more appropriate.