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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Link to relevant study record(s)

Reference
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
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
Type:
other: results of PBPK simulation
Results:
see discussion below

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)

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.

Description of key information

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.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information