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The test substance is rapidly and completely absorbed following oral ingestion, and is rapidly eliminated in the urine as unmetabolized test substance. The elimination half-life of the test substance in rats is a few hours. Rats and monkeys displayed qualitatively and quantitatively similar elimination kinetics compared to mice, which had a slower elimination rate. Based on comparative elimination kinetics across species, the rat is the rodent model most applicable to the test substance elimination kinetics in primates. Elimination kinetics were similar in single- and repeated-dose studies, indicating that the test substance did not accumulate in the blood and that the test substance was eliminated prior to receiving the next dose (24 hours).

Metabolism: The test substance was not metabolized in any of the systems tested. The test systems included rat hepatocytes (DuPont 23460), rat S9 screen (DuPont 25295) and a trout hepatocyte screen (DuPont 23459). In oral gavage studies, the administered test substance was eliminated completely as unmetabolized test substance via the urinary route of excretion (DuPont 18405-1017).

Route of Elimination: The test substance is eliminated via the urinary route. In early screening studies, rats were dosed with the test substance and urine was collected for 96 hours (DuPont 24016). The urine was then analyzed to determine how much of the administered dose was eliminated in urine. Approximately 90% of the administered dose was collected in urine, indicating that the urinary route of elimination was the primary route. In GLP rat and mouse ADME studies conducted under EPA consent order, approximately 100% (103% ± 2.7 in male and 99.8% ± 6.4 in female) of the administered test substance was recovered in rat urine (DuPont 18405-1017). Similarly, approximately 90% (89.5% ± 6.9 in males and 91.5% ± 6.0 in female) of administered test substance was recovered in mouse urine (DuPont 18647-1017).

Species influence on elimination kinetics: Rats and monkeys eliminated the test substance at similar rates, with a half-life of a few hours (2-5 hours). Conversely, mice eliminated the test substance more slowly (approximately 6-10x more slowly) with a half-life of about a day (DuPont 17751-1579; DuPont 24281; DuPont 25300). These findings indicate that the rat is the more relevant model for kinetics in primates. Based on these results, mice will not be considered relevant for other descriptions of kinetics in this document.

The influence of single vs. multiple dosing on elimination kinetics:Elimination kinetics were similar in single and repeated dose scenarios, indicating that as expected for a metabolically stable compound, repeated exposure did not affect elimination kinetics in rats. In a rat single oral dose (30 mg/kg) kinetic screen, the concentration of the test substance in plasma 2 hours post-dosing was similar (approximately 90000 ng/mL) to that seen after 6 or 7 daily gavage doses (DuPont 24281; DuPont 24009). Additionally, the rate of elimination was consistent in single and repeated oral dose studies. Based on the results of these studies the test substance did not accumulate in the blood with repeated dosing and was eliminated prior to the next dosing period approximately 24 hours later.

Influence of route of exposure on elimination kinetics:The elimination half-life in rats was the same whether the test substance was administered orally or intravenously. Based on recovery of the test substance in the urine following either i.v. or oral dosing, the test substance was completely absorbed and bioavailable and elimination kinetics were similar for both oral gavage and i.v. dosing in rats (DuPont 17751-1579; DuPont 24281).

Other Findings: Kinetic studies also demonstrated that the elimination half-life is the same whether determined in blood or urine (DuPont 18405-1017; DuPont 17751-1579; DuPont 24281).

Elimination Kinetics and Half-lives: A key objective of the kinetic studies was to provide the data necessary for meaningful comparison of elimination rates among candidate processing aids. A useful benchmark for such a comparison is the time required for a substance to clear a biological system (Clearance Time). In classical pharmacokinetic principles, first-order kinetic processes (elimination or steady-state) are virtually complete in 4 to 5 half-lives (Pratt WB and Taylor P, Principles of Drug Action-The Basis of Pharmacology, 3rdEd., Churchill Livingtone, 1990; Goodman & Gilman’s – The Pharmacological Basis of Therapeutics, 9thEd., McGraw-Hill, 1996). A conservative and useful approach for describing and comparing elimination kinetics across substances is to use a clearance time of 6 half-lives, i.e. where over 98% of the administered dose has been eliminated. The relationship between biological clearance time and half-life can be used to evaluate species and exposure effects on elimination kinetics. The following table summarizes the test substance elimination rates across multiple species and exposure scenarios.

 

Sample type

Species

Route

Frequency

Dose

(mg/kg)

Approx. half-lifea(hr)

Report

Male

Female

plasma

monkey

i.v.

single

10

2

2

DuPont-17751-1579 RV1

 

rat

i.v.

single

10

4

1

 

rat

i.v.

single

50

3

1

 

rat

oral

single

10

2

1

DuPont-24281

 

rat

oral

single

30

4

1

 

mouse

oral

single

10

24

10

DuPont-25300

 

mouse

oral

single

30

23

10

 

rat

oral

multiple

30

8

1

DuPont-24009

urine

rat

oral

single

30

3

8

DuPont-18405-1017 RV1

 

mouse

oral

single

3

21b

18b

DuPont-18647-1017 RV1

aApproximate half-life is defined as bioelimination half-life based on pharmacokinetic principle of clearance time. Clearance time is defined as 6 half-lives.

bCalculated using slope of elimination curve since <98% of the administered dose was collected in urine.

 

Based on the above robust toxicokinetics dataset, rat data is the preferred data for use in human risk assessments. Mice were shown to have a toxicokinetic profile that was distinct from both rats and monkeys.Rats and monkeys eliminated the test substance at similar rates, with a half-life of a few hours (2-5 hours).Conversely, mice eliminated the test substance more slowly (approximately 6-10x more slowly) with a half-life of about a day. Based on these results, mice will not be considered relevant for other descriptions of kinetics in this document.