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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1994
Report Date:
1994

Materials and methods

Objective of study:
metabolism
Test guideline
Qualifier:
equivalent or similar to
Guideline:
EPA OPP 85-1 (Metabolism and Pharmacokinetics)
Deviations:
no
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: AC 5561-133
- Purity: 99.5 %

RADIOLABELLING INFORMATION
- Radiochemical purity: 96.8%
- Specific activity: 43.41 µCi/mg
- Locations of the label: Pyridine ring 6-carbon
Radiolabelling:
yes
Remarks:
14C

Test animals

Species:
rat
Strain:
Sprague-Dawley
Remarks:
Crl:CD BR
Details on species / strain selection:
The laboratory rat is selected as a suitable model species for human exposure through the food chain; the rat is also a preferred mammalian species specified in the EPA Study Guidelines 85-1.
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, Massachusetts, USA
- Age at study initiation: 6 to 10 weeks
- Weight at study initiation: 200 ± 50 g
- Housing: individual glass metabolism cages constructed to allow for separate collection of urine and faeces.
- Diet: ad libitum
- Water: tap water ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 4
- Humidity (%): 50 ± 20
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
other: oral gavage and intravenous
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The radiolabeled test item was dissolved in corn oil for all oral dosing solutions and intravenous dosing solution was prepared in normal saline solution.
Duration and frequency of treatment / exposure:
Group A: oral gavage single low dose
Group B: oral gavage single high dose
Group C: Mutiple Oral Low Dose (14 days)
Group D: single intravenous Dose
Group E: Control Group (oral gavage single dose)
Doses / concentrationsopen allclose all
Dose / conc.:
9.5 mg/kg bw/day (nominal)
Remarks:
oral gavage single dose
Dose / conc.:
924 mg/kg bw/day (nominal)
Remarks:
oral gavage single dose
Dose / conc.:
10 mg/kg bw/day (nominal)
Remarks:
oral gavage daily for 14 days (unlabelled test item), followed by single dose labelled test item (9.26 mg/kg bw)
Dose / conc.:
9.94 mg/kg bw/day (nominal)
Remarks:
intravenously administered
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
single dose vehicle only (1 mL corn oil)
No. of animals per sex per dose:
Group A - D: 5
Group E: 2
Control animals:
yes, concurrent vehicle
Positive control:
Not applicable
Details on study design:
- Dose selection rationale: A preliminary study has been conducted. Furthermore, the low dose corresponds to a NOEL which is consistent with a teratology study in rats and will provide for an appropriate intravenous dosage.
Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, (blood, bone-femur, brain, fat-reproductive area, skin-shaved, testes, ovaries, heart, kidneys, liver, lungs, muscle-thigh, spleen and residual carcass,
- Time and frequency of sampling: 0-4, 4-8, 8-12, 12-24, 24-36, 36-48, 48-72, 72-96, 96-120, 120-144, and 144-168 hours post-dosing

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces
- Time and frequency of sampling: Day 1 and Day 2
- From how many animals: samples pooled per sex/group
- Method type(s) for identification: HPLC, TLC
Statistics:
limited to mean and standard deviation

Results and discussion

Preliminary studies:
Results from the preliminary study indicated that approximately 72 % to 75 % of the 14C-test item-related radioactivity was excreted in the urine and cage rinse over a 3-day period. About 19 % to 20 % was excreted in the feces. Expired air contained 0.06 % to 0.12 % of the dosed radioactivity. An average of ~90 % of the dosed radioactivity was excreted within the first 24 hours. The excretion pattern was similar in both male and female rats. The excretion pattem and quantity for this 72-hour period is consistent with those of the oral low dose groups in the definitive study.
Main ADME resultsopen allclose all
Type:
excretion
Results:
The majority of the administered dose was excreted mainly as intact item in faeces and urine (78.3 % to 96.0 %) in the first 24 h.
Type:
metabolism
Results:
Two metabolites (the substituted and nonsubstituted 2-carbamoyl derivatives) accounted for 0.24 % and 0.15 % of urine, respectively.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The calculated percent of absorption in the oral dose groups was 80.6% and 80.0% for single-dose males and females, respectively, and 75.6% and 71.4% for multiple-dose males and females, respectively.
Details on distribution in tissues:
Analysis of rat tissues and organs (blood, bone-femur, brain, fat-reproductive area, skin-shaved, testes, ovaries, heart, kidneys, liver, lungs, muscle-thigh, spleen and residual carcass) showed that TRR levels were below detection limits except in carcass (<0.01 - 0.87 ppm) and high dose liver (0.45 ppm in female rats) and kidney (0.36 ppm for male rats and 0.52 ppm for female rats) and multiple dose ovaries (0.03 ppm). Total radioactive residue levels in control (untreated) animal samples were all less than the validated minimum quantifiable limit of detection.
Details on excretion:
A majority of the administered dose was eliminated in urine (67.8 %-94.6 %) and, to a lesser extent, in feces (5.5 %-33.2 %) over a 7-day period following dosing. Most of the elimination occurred within the first 24 hours post treatment.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Two metabolites (the substituted and nonsubstituted 2-carbamoyl derivatives) accounted for 0.24 % and 0.15 % of urine, respectively. Low, but detectable, levels of several unknown metabolites (0.21 to 5.65 % of urine) were also found in urine samples; however none of the individual unknown metabolites exceeded 0.11 % of urinary radiocarbon.

Any other information on results incl. tables

Table 1: Cumulative Amount of Radioactivity at Specified Intervals after Rats Were Dosed with 14C-Test item – Percent of Radioactive Dose in Urine

Collection Interval (hours)

Group A
single oral dose
9.5 mg/kg

Group A
single oral dose
9.5 mg/kg

Group B
single oral dose
924 mg/kg

Group B
single oral dose
924 mg/kg

Group C
multiple oral dose
9.26 mg/kg

Group C
multiple oral dose
9.26 mg/kg

Group D
single intravenous dose
9.94 mg/kg

Group D
single intravenous dose
9.94 mg/kg

 

Male

Female

Male

Female

Male

Female

Male

Female

0- 4

39.4

12.2

14.4

21.5

20.3

17.6

66.2

41.2

0- 8

63.5

27.4

62.5

55.1

39.5

30.9

86.7

70.0

0-12

69.3

60.0

69.8

62.3

58.6

44.8

88.8

72.6

0-24

73.7

67.7

74.5

68.3

68.9

56.9

90.6

75.0

0-36

75.2

70.2

75.4

69.5

70.8

59.7

91.3

75.5

0-48

76.3

71.9

75.9

70.3

71.7

61.0

91.8

76.8

0-72

77.1

72.9

76.2

71.6

72.2

62.1

92.3

77.7

0-96 

77.5

73.6

76.5

72.1

72.6

62.6

92.5

78.6

0-120

77.7

73.8

76.6

72.6

72.9

63.1

92.6

78.9

0-144

77.9

74.1

76.8

72.9

73.0

63.4

92.7

79.1

0-168

81.1

78.5

78.8

76.7

75.0

67.8

94.6

86.5

 

Table 2: Cumulative Amount of Radioactivity at Specified Intervals after Rats Were Dosed with 14C-Test item – Percent of Radioactive Dose in faeces

Collection Interval (hours)

Group A
single oral dose
9.5 mg/kg

Group A
single oral dose
9.5 mg/kg

Group B
single oral dose
924 mg/kg

Group B
single oral dose
924 mg/kg

Group C
multiple oral dose
9.26 mg/kg

Group C
multiple oral dose
9.26 mg/kg

Group D
single intravenous dose
9.94 mg/kg

Group D
single intravenous dose
9.94 mg/kg

 

Male

Female

Male

Female

Male

Female

Male

Female

0- 4

0.4

<0.01

<0.01

<0.01

0.1

0.1

2.7

<0.01

0- 8

1.1

<0.01

0.2

<0.01

0.1

0.7

4.0

<0.01

0-12

5.3

0.1

2.0

0.1

0.4

1.2

4.3

0.2

0-24

22.7

20.3

18.8

17.9

23.8

23.3

5.4

3.0

0-36

24.4

22.6

19.9

20.0

27.5

27.5

5.9

3.4

0-48

25.3

24.0

20.6

20.6

29.4

30.7

6.2

3.6

0-72

25.8

24.7

20.8

21.1

30.1

31.5

6.3

4.7

0-96 

26.0

25.3

20.8

21.3

30.5

32.0

6.4

4.9

0-120

26.2

25.4

21.0

21.7

30.8

32.2

6.6

5.1

0-144

26.3

25.6

21.1

21.8

30.9

33.1

6.6

5.2

0-168

26.4

25.9

21.1

21.9

31.1

33.2

6.6

5.5

 

Applicant's summary and conclusion