bis(branched-alkyl) 2-{[(1-phenylethyl)amino]methyl}alkanedioate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: expert statement

Adequacy of study:

key study

Study period:

15 February 2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Data source

Reference

Reference Type:

other: expert statement

Title:

Unnamed

Year:

2019

Report date:

2019

Materials and methods

Principles of method if other than guideline:

Toxicokinetics were analyzed using the PK-Sim™ platform (Willmann et. al 2003). PK-Sim® was developed by Bayer AG and is a comprehensive software tool for whole-body physiologically based pharmacokinetic (PBPK) modeling.

GLP compliance:

no

Test material

Test material information

Constituent 1

Test material form:

liquid

Details on test material:

- Appearance/physical state: Pale amber liquid
- Storage conditions: approximately 4 °C in the dark

Results and discussion

Main ADME results

Type:

other: results of PBPK simulation

Results:

see discussion below

Any other information on results incl. tables

PBPK Simulation

 

In-vivo metabolism data were not available. However, AMES testing with and without S9 fractions gave similar negative results in terms of revertants and toxicity (Envigo Rpt No 41404227, Thompson 2015).  These results suggest the substance is unlikely to be metabolically activated to toxic intermediates but cannot define the effectiveness of metabolically facilitated elimination. Based on this information, the simulation was run assuming passive distribution via systemic circulation, accumulation in adipose tissue and elimination via urine and feces.

As can be seen from simulation results provided in Figure 1 (attached), within 28 days, venous blood levels reached a steady state concentration of 6E-06 mmol/L. By the same 28-day period, levels in adipose tissue reached a steady state level of approximately 9.6 mmol/L. 96% of the substance was eliminated via feces and no significant substance elimination via urine was evident.

References

Willmann et. al. PK-Sim®: a physiologically based pharmacokinetic ‘whole-body’ model. Biosilico. 2003; 1 (4): 121-124.

 

Colclough et. al. (2014) Species differences in drug plasma protein binding. Medicinal Chemistry Communications (5) 963-967.

 

NRC 1995. Nutrient Requirements of Laboratory Animals: Fourth Revised Edition. National Research Council (US) Subcommittee on Laboratory Animal Nutrition.  Washington (DC): National Academies Press (US)

Applicant's summary and conclusion

Conclusions:

The simulation results showed that, within 28 days, venous blood levels reached a steady state concentration of 6E-06 mmol/L. By the same 28-day period, levels in adipose tissue reached a steady state level of approximately 9.6 mmol/L. 96% of the substance was eliminated via feces and no significant substance elimination via urine was evident.

Executive summary:

Toxicokinetics were analyzed using the PK-Sim™ platform (Willmann et. al 2003). PK-Sim® was developed by Bayer AG and is a comprehensive software tool for whole-body physiologically based pharmacokinetic (PBPK) modeling. In-vivo metabolism data were not available. However, AMES testing with and without S9 fractions gave similar negative results in terms of revertants and toxicity. These results suggest the substance is unlikely to be metabolically activated to toxic intermediates but cannot define the effectiveness of metabolically facilitated elimination. Based on this information, the simulation was run assuming passive distribution via systemic circulation, accumulation in adipose tissue and elimination via urine and feces. The simulation results showed that, within 28 days, venous blood levels reached a steady state concentration of 6E-06 mmol/L. By the same 28-day period, levels in adipose tissue reached a steady state level of approximately 9.6 mmol/L. 96% of the substance was eliminated via feces and no significant substance elimination via urine was evident.