Registration Dossier

Diss Factsheets

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report date:
1999

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: Commission Directive 87/302/EEC, Part B: Methods for the Determination of Toxicity
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.7485 (Metabolism and Pharmacokinetics)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese MAFF: Requirement for Safety Evaluation of Agricultural Chemicals
GLP compliance:
yes (incl. QA statement)
Remarks:
The Department of Health of The Government of the United Kingdom

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
446-630-3
EC Name:
-
Cas Number:
181587-01-9
Molecular formula:
C13H9Cl2F3N4OS
IUPAC Name:
5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(ethanesulfinyl)-1H-pyrazole-3-carbonitrile
Details on test material:
- Name of test material (as cited in study report): RPA 107382 (non-radiolabelled)
- Analytical purity: 99.7%
- Batch No.: 2CFS94
- Name of test material (as cited in study report): [14C]-RPA 107382 (radiolabelled)
- Radiochemical purity: 99.3%
- Batch No.: GRX 485A
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited
- Weight at study initiation: 206 - 242 g (males); 166 - 193 g (females)
- Housing: During acclimatisation, animals were housed up to 2 to a cage in polypropylene and stainless steel cages with wood shavings as bedding. Following dose administration, the animals were housed singly in glass metabolism cages designed for the separate collection of urine and faeces.
- Individual metabolism cages: yes
- Diet: SDS Rat and Mouse Maintenance Diet No. 1 (Special Diet Services), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 7 d

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.05% or 0.5% (w/w) aqueous methyl cellulose solution containing 0.01% (w/w) Tween 80
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: [14C]-labelled test substance was dissolved in acetone in a volumetric flask and the flask made up to volume with acetone. The radiodiluted solution was added drop-wise, with stirring, to a pre-weighed 0.05% or 0.5% (w/w) aqueous methyl cellulose solution containing 0.01% (w/w) Tween 80. The resulting suspension was placed under a stream of nitrogen until all traces of acetone had evaporated. The suspension was re-weighed and adjusted for water lost during the evaporation.
The non-radiolabelled test substance suspension was formed as described for the radioactive test substance suspensions, by addition of a solution of the test substance in acetone to dose vehicle, followed by evaporation of the acetone. The resulting solution was re-adjusted for any water lost.

HOMOGENEITY AND STABILITY OF TEST MATERIAL: A trial dose formulation was prepared at the high dose level by dissolving about 430 mg of non-radiolabelled test substance and a small amount of [14C]-labelled test substance in acetone. This solution was added drop-wise with stirring to about 3.44 g of 0.5% (w/w) aqueous methyl cellulose solution containing 0.01% (w/w) Tween 80. The acetone was evaporated under nitrogen and the weight of the formulation adjusted for any loss of water. Six weighed samples were taken for LSC to confirm the homogeneity of the resulting suspension. The homogeneity and purity were confirmed again after 7 d storage at +4°C. The purity of a high dose level formulation was also shown to be 100% following 18 d storage.
Duration and frequency of treatment / exposure:
5 and 1000 mg/kg bw: single oral administration
5 mg/kg bw/d: daily for 15 d
Doses / concentrations
Remarks:
Doses / Concentrations:
5 and 1000 mg/kg bw (single oral administration of the radiolabelled test substance)
5 mg/kg bw/d: daily non-labelled test substance for 14 d, followed by a single administration of the labelled test substance
No. of animals per sex per dose / concentration:
5
Control animals:
no
Positive control reference chemical:
no
Details on dosing and sampling:
PHARMACOKINETIC STUDY (absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, cage washes and tissues (adrenals, bone and marrow, brain, gastrointestinal tract and contents, heart, kidneys, liver, lung, muscle (leg), pancreas, perirenal fat, plasma, skin and fur, spleen, stomach and contents, testes/ovaries, thyroid, whole blood, residual carcass)
- Time and frequency of sampling: urine at 6, 12, 24, 48, 72, 96, 120, 144 and 168 h post radioactive dose; faeces and cage washes at 12, 24, 48, 72, 96, 120, 144 and 168 h post radioactive dose; tissues at 168 h post radioactive dose

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces
- Time and frequency of sampling: 5 mg/kg bw (single and repeated dose): 0-12, 12-24, 24-48 and 48-72 h (urine and faeces); 1000 mg/kg bw: 0-24, 24-48 and 48-72 h (urine), 0-12, 12-24, 24-48 and 48-72 h (faeces)
- From how many animals: 5 animals (pooled per sex and dose)
- Method type(s) for identification: HPLC-MS, radio-HPLC

Results and discussion

Preliminary studies:
In order to establish the experimental methodology for the main study, a pilot study was carried out by administering 5 mg/kg bw [14C]-labelled test substance to 2 male and 2 female rats. Following administration, the animals were transferred to individual all-glass metabolism cages. Urine and faeces were collected at daily intervals for 7 d. Expired air was collected daily into 2 serial traps containing 2-ethoxyethanol:ethanolamine (7:3, v/v) for 2 d. After the 168 h collection period, the animals were killed by CO2 narcosis and the carcasses retained.
The mean recovery of total radioactivity over the 168 h collection period was 90.2% (males) and 89.3% (females), respectively. Absorption and excretion were rapid with about 78-85% of the dose recovered within the first 48 h post dose. The predominant route of excretion was via faeces with means of 68.9% (males) and 49.2% (females) over the 168 h collection period. Excretion of total radioactivity via urine accounted for about 20.7% (males) and 38.3% (females) of the dose over this period. The low amount of the dose recovered in expired air (<0.1%), did not warrant expired air to be collected in the main study. At the end of the collection period (168 h), less than 1.1% of the administered dose was retained in the carcass.
Main ADME resultsopen allclose all
Type:
absorption
Results:
5 mg/kg bw: low amounts of radioactivity in the contents of gastrointestinal tract; 1000 mg/kg bw: no residual radioactivity in the contents of GI tract
Type:
distribution
Results:
widespread tissue distribution of radioactivity in males and females of all groups, low concentrations of radioactivity in all tissues collected
Type:
metabolism
Results:
5 mg/kg bw: extensive metabolism, wide metabolite pattern in urine and faeces; 1000 mg/kg bw: extensive metabolism, wide metabolite pattern in urine, majority of the test substance found unmetabolized in faeces
Type:
excretion
Results:
5 mg/kg bw: most of the radioactivity was excreted 48 h after administration, mainly via faeces; 1000 mg/kg bw: most of the radioactivity was excreted 72 h after administration, urinary excretion played a minor role

Toxicokinetic / pharmacokinetic studies

Details on absorption:
5 mg/kg bw: After 168 h post dose, low amounts of radioactivity were found in the contents of gastrointestinal tract, with a mean value of 0.04% of the administered dose in both male and female rats. Levels of radioactivity within the contents of the stomach were close to the limit of reliable determination for all animals.

1000 mg/kg bw: Radioactivity was not observed in the contents of the gastrointestinal tract or stomach suggesting that absorption of the radiolabelled dose was complete by 168 h post dose.

5 mg/kg bw following 14 d oral administration of non-radiolabelled test substance at a target dose level of 5 mg/kg:
Low amounts of radioactivity were found in the contents of gastrointestinal tract of both sexes, with means of 0.07% and 0.03% of the dose for male and female rats, respectively, while levels of radioactivity within the contents of the stomach were close to the limit of reliable determination.
Details on distribution in tissues:
5 mg/kg bw: At 168 h post dose, the tissue distribution of radioactivity in males and females was widespread with low concentrations of radioactivity observed in all tissues collected.
In males, the highest concentrations of radioactivity were found in the kidney, liver and skin and fur (0.062, 0.058 and 0.040 µg equiv./g), respectively. In plasma and whole blood of males, concentrations of 0.036 and 0.041 µg equiv./g radioactivity were found. All other tissues contained concentrations of radioactivity which were similar to or below that observed in plasma.
In females, the highest concentrations of radioactivity were found in kidney, lung, thyroid gland, spleen, liver, heart, skin and fur and adrenal gland (means of 0.087, 0.068, 0.063, 0.062, 0.061, 0.049, 0.049 and 0.043 µg equiv./g), respectively. In plasma and whole blood of females, concentrations of 0.027 and 0.266 µg equiv./g radioactivity were found. All other tissues contained concentrations of radioactivity which were similar to or below that observed in plasma.
Levels of radioactivity remaining in the carcass accounted for less than 1.3% in all animals.

1000 mg/kg bw: In males, the highest concentrations of radioactivity were located in the skin and fur, liver and thyroid gland (9.9, 1.8 and 1.8 µg equiv./g, respectively). In plasma, concentrations of radioactivity of 1.2 µg equiv./g were detected. All other tissues contained concentrations of radioactivity which were similar to or below that observed in plasma, with concentrations in individual animals close to the limit of reliable determination for many tissues.
The distribution of radioactivity in female rats followed a similar pattern to the males, with concentrations in many of the tissues close to the limit of reliable determination for individual animals. The highest concentrations were found in the thyroid gland, skin and fur, adrenals, liver, ovaries, kidney and whole blood (3.4, 2.3, 1.7, 1.7, 1.5, 1.3 and 1.3 µg equiv./g, respectively). In plasma, concentrations of radioactivity of 0.5 µg equiv./g were detected. The remaining tissues contained concentrations which were similar to or below that of plasma.
No significant radioactivity was detected in the carcasses from male and female rats.

5 mg/kg bw following 14 d oral administration of non-radiolabelled test substance at a target dose level of 5 mg/kg:
Following sacrifice of the animals at 168 h post radiolabelled dose, concentrations of radioactivity present in tissues were similar to those observed following the single administration of radiolabelled test substance at the low dose level for female animals, but slightly higher in males. Low concentrations of radioactivity were measured in all tissues, with the highest concentration for both males and females observed in the skin and fur (0.29 µg equiv./g (males) and 0.32 µg equiv./g (females). Concentrations in all other tissues collected were similar to those present in plasma (0.09 and 0.03 µg equiv./g for males and females, respectively), with the exception of whole blood in female animals (0.195 µg equiv./g).
Levels of radioactivity remaining in the carcass accounted for less than 0.8% in all animals, suggesting that no accumulation of the test material had occurred.
Details on excretion:
5 mg/kg bw: The results for the cumulative recovery of total radioactivity were consistent with the findings of the pilot experiment. The predominant route of elimination for both males and females was via faeces with means of 67.3% (males) and 54.9% (females) of the administered dose excreted by this route by 168 h post dose. Urinary excretion resulted in the recovery of 23.5% and 36.4% of the administered dose in males and females, respectively.
Excretion of the dose was rapid with mean values of 85.6% (males) and 86.4% (females) of the administered radioactivity recovered within 48 h post dose. By the end of the 168 h collection period, the overall mean recovery in males and females was 92.3% and 94.1%, respectively.

1000 mg/kg bw: In the high dose group, the major route of elimination was again via faeces, with means of 88.4% (males) and 87.5% (females) of the dose excreted by this route. Urinary excretion played a minor role in elimination with only 3.0% and 5.1% of the dose recovered from males and females, respectively. The excretion of total radioactivity was slower than that observed following administration at the low dose level. By 48 h post dose, 77.3% (males) and 64.0% (females) of the administered dose had been recovered, which increased by 72 h post dose to mean values of 87.5% and 90.2% in male and female rats, respectively.
By the end of the 168 h collection period, the overall mean recovery in male and female rats was 91.7% and 93.0%, respectively.

5 mg/kg bw following 14 d oral administration of non-radiolabelled test substance at a target dose level of 5 mg/kg:
Results for the recovery of total radioactivity following administration of radiolabelled test substance to male and female rats at a target dose level of 5 mg/kg after the multiple oral administration of non-radiolabelled test substance were similar to those obtained following the single administration of radiolabelled test substance at the low dose level. The predominant route of elimination for all animals was via faeces, with means of 70.7% (males) and 55.5% (females) of the dose excreted by this route. Urinary excretion resulted in the recovery of 22.5% and 35.1% of the administered dose in males and females, respectively.
Excretion of the dose was rapid with means of 81.6% (males) and 85.9% (females) of the radioactivity recovered within the first 48 h post dose. By the end of the 168 h collection period, the overall mean recovery in male and female rats was 94.1% and 93.7%, respectively.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
5 mg/kg bw:
The radio-HPLC profile of the urine of low dose males and females revealed an extensive pattern of metabolism, covering a wide range of metabolite polarities (Table 1). Ten to 12 significant metabolites were observed in male and female rats. Four and 5 of the metabolites in male and female urine, respectively, were identified as RPA 112705, RPA 114345, RPA 104615, MB 45897 (in both sexes) and RPA 97973 (in female urine only). RPA 112705 was present in female urine in far greater abundance than male urine (6.8% dose in female, 1% dose in male). Six further components were observed in male and female urine (U1, U2, U4, U5, U6 and U7). A further component designated U8 was observed only in female urine. The most predominant urinary metabolites were the polar components U1 and U2 (7.19% and 4.94% of dose in males, 4.18% and 6.20% of dose in females).
The radio-HPLC analysis of faeces of males and females treated with the low dose revealed extensive metabolism with components covering a wide range of polarities (Table 2). As retention times varied it was not possible to determine if components which did not co-chromatograph with standards, were different metabolites at each timepoint. In total these components accounted in male and female faeces for about 7% of dose between 0-72 h. The remaining components co-chromatographed with metabolite standards and were identified as RPA 112705, RPA 114345, MB 45897, RPA 97973 and RPA 107566. Small variations in the pattern of excretion between individual timepoints and sexes were noticed. The unmetabolized test substance was only detected in the 0-12 hour timepoint and RPA 112705 was not detected until the 12-24 hour timepoint. One major difference was noticed between male and female low dose faeces was the increased abundance of RPA 112705 in male animals (about 22% of dose) compared to female animals (about 10% of dose). This contrasts with urine where RPA 112705 was much more abundant in female animals.

1000 mg/kg bw:
The radio-HPLC profiling of high dose group male and female urine revealed a pattern of metabolism similar to that seen in low dose animals (Table 1). Nine significant metabolites were observed, each of which was also observed at the low dose level. In the urine of male rats, the components RPA 112705, RPA 114345, RPA 104615 and MB 45897 were detected. In female urine, only the components RPA 112705 and MB 45897 were observed. As observed for the low dose group, the abundance of RPA 112705 was far greater in female animals than males (0.8% of dose in females; 0.04% of dose in males). Some further components were identified as U1, U2, U4, U6 and U7 in both sexes and U8 in females only. As observed in the urine of the low dose group, the major components in high dose male and female urine were the polar metabolites U1 and U2 (1.08 and 0.12% of dose in males; 1.31 and 0.46% of dose in females, respectively). The component U5, observed in the low dose urine, was not detected at the high dose level. No unchanged test substance was detected.
The radio-HPLC profile of the faeces of the high dose group indicated the major component was unchanged parent material, which accounted for 72.24 and 77.0% of the dose between 0-72 h in male and female faeces, respectively (Table 2). The major metabolites seen in the faeces of the low dose group were also present in male faeces at the high dose level with RPA 112705, RPA 114345, MB 45897, RPA 97973 and RPA 107566. The females of the high dose group excreted only the metabolites MB 45897 and RPA 107566 via faeces.

5 mg/kg bw (repeated dose):
The radio-HPLC profile of the males and females of the low repeated dose group showed a very similar qualitative and quantitative metabolite pattern in urine to that observed for the single low dose group (Table 1). Eleven significant metabolites were detected in males and 12 in females. In male urine, the metabolites RPA 112705, RPA 114345, RPA 104615, MB 45897 and RPA 97973 were observed. Furthermore, the components named U1, U2, U4, U5, U6 and U7 were detected. In the female urine, additionally the component U8 was detected. The abundance of RPA 112705 was far greater in female urine (about 8% of dose) compared to male (about 0.5% of dose). In addition the component U6 also appeared in greater abundance in female urine. These differences were also noted in comparisons between male and female urine at the single low dose and high dose levels. As observed for the single dose samples, the predominant urinary metabolites following repeated doses were the polar metabolites U1 (7.73 and 4.83% of dose in male and female urine, respectively) and U2 (3.48 and 5.23% of dose in male and female urine, respectively).
Radio-HPLC profiling of the faeces of the males and females of the low repeat dose group revealed an extensive pattern of metabolism which was similar to that observed following a single dose (Table 2). There were 9 and 7 unknown metabolites in male and female faeces, accounting for a total of about 9 and 7% of dose, respectively, between 0-72 h. The remaining components were identified as RPA 112705, RPA 114345, MB 45897, RPA 97973 and RPA 107566. The time dependant variation in metabolite pattern which was obvious following the single dose was again observed. Unchanged test substance was only detected at the 0-12 h timepoint while RPA 112705 was not detected until 12-24 hours post dose. It was also noted that the abundance of RPA 112705 was considerably less in females (11.5% of dose) than that observed for male animals (22.55% of dose).

Any other information on results incl. tables

Table 1: Quantitative distribution of radioactivity following radio-HPLC analysis of urine samples

Sample timepoint

Component

individual components as % of dose

5 mg/kg bw

1000 mg/kg bw

5 mg/kg bw (rep. dose)

males

females

males

females

males

females

0-12 h

RPA 112705

0.33

1.08

 

 

0.14

2.56

RPA 114345

0.41

0.49

0.35

0.38

RPA 97973

---

0.58

0.07

0.42

RPA 104615

0.52

0.83

0.54

0.85

MB 45897

1.03

2.09

1.09

3.29

U1

2.00

0.61

1.25

0.99

U2

3.21

3.72

2.49

2.40

U4

0.82

0.43

0.53

0.36

U5

0.26

---

0.16

0.53

U6

0.20

0.29

0.09

0.50

U8

---

1.12

---

0.63

unknown (sum)

---

---

---

---

12-24 h
(0-24 h for high dose)

RPA 112705

0.53

3.25

---

0.09

0.21

3.66

RPA 114345

0.48

0.86

0.04

---

0.33

0.42

RPA 97973

---

0.63

---

---

---

0.30

RPA 104615

0.37

0.68

0.05

0.04

0.26

0.57

MB 45897

0.50

0.88

0.17

0.25

0.45

1.79

U1

2.96

1.63

0.12

0.07

2.75

1.43

U2

1.51

1.79

0.03

---

0.82

1.36

U4

1.27

0.42

0.06

0.05

1.24

0.33

U5

0.21

0.35

---

---

0.14

0.54

U6

0.21

1.16

0.02

0.05

0.15

1.00

U7

0.10

0.14

---

---

0.16

0.19

U8

---

---

---

0.04

---

0.52

unknown (sum)

---

---

---

0.03

0.15

---

RPA 112705

0.13

2.28

0.02

0.31

0.12

2.19

24-48 h

RPA 114345

0.07

0.35

0.02

---

---

0.20

RPA 97973

---

---

---

---

---

0.11

RPA 104615

0.12

0.38

0.06

0.08

0.14

0.16

MB 45897

0.15

0.36

0.22

0.50

0.11

0.20

U1

2.09

1.78

0.39

0.43

2.96

1.90

U2

0.22

0.66

0.03

0.04

0.14

1.29

U4

1.05

0.47

0.07

0.05

1.97

0.53

U5

0.05

0.29

---

---

---

0.46

U6

0.12

0.84

---

0.12

0.17

0.82

U7

0.12

0.09

0.03

0.06

0.23

0.13

U8

---

0.70

---

0.03

---

0.09

unknown (sum)

0.34

0.19

0.02

---

0.30

0.10

RPA 112705

---

0.16

2.44

0.42

0.04

0.29

RPA 114345

0.01

0.04

---

---

---

0.06

48-72 h

RPA 97973

---

0.02

---

---

---

0.03

RPA 104615

---

0.03

0.03

0.12

0.03

0.07

MB 45897

---

0.04

0.10

0.09

---

---

U1

0.14

0.16

0.57

0.81

0.77

0.51

U2

---

0.03

0.06

0.42

0.03

0.18

U4

0.09

0.06

0.04

0.07

0.46

0.11

U5

---

0.02

---

---

---

0.05

U6

0.01

0.07

---

0.12

0.07

0.16

U7

0.03

---

0.02

0.06

0.13

---

U8

---

0.09

---

---

---

---

unknown (sum)

0.09

---

0.08

---

0.34

---

U1: Glucuronide conjugate of hydroxy-MB45897

U2: Sulphinic acid of RPA 104615

U4: Sulphate conjugate of hydroxy-MB 45897

U5: Unknown, related to U4

U6: Cyclic structure, related to U7

U7: Cyclic amide of RPA 112705

U8: Sulphate conjugate of RPA 114345

Table 2: Quantitative distribution of radioactivity following radio-HPLC analysis of faeces samples

Sample timepoint

Component

individual components as % of dose

5 mg/kg bw

1000 mg/kg bw

5 mg/kg bw (rep. dose)

males

females

males

females

males

females

0-12 h

parent component

0.29

0.19

25.55

10.38

1.21

0.38

RPA 114345

0.53

0.56

---

---

0.26

0.60

RPA 107566

0.35

0.13

---

---

0.31

1.43

RPA 97973

0.92

0.58

---

---

0.23

0.78

MB 45897

1.01

1.01

---

---

0.20

0.94

unknown (sum)

0.26

0.93

---

---

0.25

0.24

12-24 h

parent component

---

---

13.88

21.93

---

3.59

RPA 114345

4.64

3.88

---

---

5.50

3.89

RPA 107566

---

0.39

0.34

0.34

---

2.13

RPA 97973

3.38

3.16

0.08

---

---

1.41

RPA 112705

10.06

2.67

0.14

---

10.76

1.20

MB 45897

6.38

4.58

---

---

2.05

4.61

unknown (sum)

3.79

3.67

---

---

3.81

0.67

24-48 h

parent component

---

---

27.8

23.54

---

---

RPA 114345

0.97

2.67

0.20

---

2.18

1.47

RPA 107566

---

---

0.67

1.02

---

---

RPA 97973

0.76

1.59

0.28

---

1.52

---

RPA 112705

11.8

6.51

1.24

---

10.70

9.92

RPA 112917

---

0.77

---

---

---

---

MB 45897

1.58

1.95

1.14

0.26

1.89

0.57

unknown (sum)

2.68

1.97

---

---

2.41

5.51

48-72 h

parent component

---

---

5.01

21.12

---

---

RPA 114345

0.31

0.43

0.07

---

0.27

0.62

RPA 107566

---

---

0.21

1.09

---

---

RPA 97973

---

---

0.10

---

---

---

RPA 112705

0.38

0.94

0.74

---

0.94

0.38

MB 45897

0.23

0.46

0.33

0.79

0.29

0.33

unknown (sum)

0.86

0.47

0.18

---

2.27

0.27

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Oral administration of 5 mg/kg bw of the radiolabelled test substance indicated a rapid absorption and excretion of the test substance. The bulk of the radioactivity was excreted 48 h after administration. In males, 62.4% of the dose were excreted via faeces and 23.5% of the dose via urine. In females, 50.2% of the dose were excreted via faeces and 36.4% of the dose via urine. This may indicate a possible sex dependent difference in the routes of excretion.
The repeated dosing with unlabelled test substance followed by a single administration of 5 mg/kg bw of the radiolabelled test substance gave patterns of absorption and excretion very similar to those observed following a single low dose. 48 h after administration, 70.7% and 55.5% of the dose were excreted via faeces and 22.5% and 35.1% of the dose via urine of males and females, respectively.
The administration of 1000 mg/kg bw of the radiolabelled test substance indicated a slower absorption than that observed at the low dose level, with the bulk of the dose being excreted by 72 h post dose (87.5% in males and 90.2% in females). In this dose group, the major route of elimination was via faeces and the excretion via urine played a minor role.
At 168 h post dose, the tissue distribution of radioactivity in males and females of all dose groups was widespread with low concentrations of radioactivity observed in all tissues collected. The highest residues of radioactivity were found in all animals in livers and kidneys.
The metabolite pattern in urine of all dose groups showed a wide range of polar components that indicate an extensive metabolism within 72 h. According to the different routes of excretion in the low and high dose groups, only a small amount of the test substance was found unmetabolized in the faeces of the two low dose groups within 72 h, whereas the majority of the test substance was found unmetabolized in the faeces of the high dose group. The high amount of the unmetabolized test substance in the faeces of the high dose group indicate a saturation of of the absorption pathways.