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EC number: 446-630-3 | CAS number: 181587-01-9
Toxicological information
Basic toxicokinetics
Currently viewing:
Administrative data
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 21 Oct 1997 - 04 Mar 1999
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 21 Oct 1997 - 04 Mar 1999
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Objective of study:
- toxicokinetics
- 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)
- Version / remarks:
- Adopted in 1984
- 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
- Radiolabelling:
- yes
- Remarks:
- 14C radiolabelled test substance
- 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: males: 195 - 235 g, females: 155 - 179 g
- Housing: During acclimatisation, animals were housed up to 2 per cage in polypropylene and stainless steel cages with wood shavings as bedding. Following dose administration, the animals were housed singly in polypropylene and stainless steel cages with raised wire mesh grids to inhibit coprophagy.
- Individual metabolism cages: yes
- Diet: SDS Rat and Mouse Maintenance Diet No. 1 (Special Diet Services, Witham, UK), ad libitum
- Water: tap water in drinking water quality, ad libitum
- Acclimation period: at least 7 days
ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 21 Oct 1997 To: 04 Mar 1999 - 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 days storage at +4 °C. The purity of a high dose level formulation was also shown to be 100% following 18 days storage. - Duration and frequency of treatment / exposure:
- single oral administration
- Remarks:
- Doses / Concentrations:
5 and 1000 mg/kg bw - No. of animals per sex per dose / concentration:
- 5
- Control animals:
- no
- Positive control reference chemical:
- no
- Details on dosing and sampling:
- PHARMACOKINETIC STUDY (distribution)
- Tissues and body fluids sampled: blood
- Time and frequency of sampling: 0.5, 1, 2, 4, 6, 8, 24, 48, 72, 96, 120, 144 and 168 h post dosing - Type:
- distribution
- Results:
- 5 mg/kg bw: peak mean concentrations of 2.11 and 1.63 µg equiv./g at 8 h post-dose in males and females, respectively; 1000 mg/kg bw: peak mean concentrations of 38.7 and 29.8 µg equiv./g at 24 and 48 h post-dose in males and females, respectively
- Details on absorption:
- 5 mg/kg bw:
The single oral administration of 5 mg/kg bw of the radiolabelled test substance leads to a rapid increase in whole blood from mean concentrations of 0.48 and 0.62 µg equiv./g tissue in males and females, respectively, at 0.5 h to peak mean concentrations of 2.11 (males) and 1.63 (females) µg equiv./g tissue at 8 h post dosing. The mean concentrations declined in a biphasic manner with concentrations decreasing rapidly to 1.47 µg equiv./g tissue (males) and 1.03 µg equiv./g tissue (females) at 24 h post dosing. Thereafter, the rate of decline slowed, with low concentrations of radioactivity in the whole blood from males and females (0.09 and 0.17 µg equiv./g tissue, respectively) observed at 168 h post dosing.
1000 mg/kg bw:
Following single oral administration of 1000 mg/kg bw of the radiolabelled test substance, mean concentrations of radioactivity of 4.3 and 3.3 µg equiv./g tissue in male and female rats were measured in whole blood at 0.5 h post dosing, respectively. Concentrations increased gradually to mean values of 14.7 µg equiv./g tissue (males) and 9.9 µg equiv./g tissue (females) at 4 h and further to 20.1 µg equiv./g tissue (males) and 12.0 µg equiv./g tissue (females) at 8 h post dosing. The peak mean concentrations of 38.7 µg equiv./g tissue in males and 29.8 µg equiv./g tissue in females were observed at 24 and 48 h post dosing, respectively. Following each peak, concentrations decreased slowly to means of 12.2 and 20.9 µg equiv./g tissue in male and female rats, respectively at 72 h post dosing. Thereafter, the rate of decline remained at a steady level, with mean concentrations of 2.9 and 3.0 µg equiv./g tissue observed in the whole blood of males and females, respectively, at 168 h post dosing. - Key result
- Test no.:
- #1
- Toxicokinetic parameters:
- Tmax: 5 mg/kg bw: 8 h (males and females)
- Key result
- Test no.:
- #1
- Toxicokinetic parameters:
- Tmax: 1000 mg/kg bw: 33.6 h (males) and 48 h (females)
- Key result
- Test no.:
- #1
- Toxicokinetic parameters:
- Cmax: 5 mg/kg bw: 2.114 µg equiv./g tissue (males) and 1.633 µg equiv./g tissue (females)
- Key result
- Test no.:
- #1
- Toxicokinetic parameters:
- Cmax: 1000 mg/kg bw: 41.66 µg equiv./g tissue (males) and 29.78 µg equiv./g tissue (females)
- Key result
- Test no.:
- #1
- Toxicokinetic parameters:
- AUC: 5 mg/kg bw: 94.88 µg equiv. × h/mL (males) and 79.38 µg equiv. × h/mL (females)
- Key result
- Test no.:
- #1
- Toxicokinetic parameters:
- AUC: 1000 mg/kg bw: 2620 µg equiv. × h/mL (males) and 2240 µg equiv. × h/mL (females)
- Key result
- Test no.:
- #1
- Toxicokinetic parameters:
- half-life 1st: 5 mg/kg bw: 48.45 h (males) and 113.98 h (females)
- Key result
- Test no.:
- #1
- Toxicokinetic parameters:
- half-life 1st: 1000 mg/kg bw: 49.18 h (males) and 44.33 h (females)
- Metabolites identified:
- not measured
- Conclusions:
- The investigation of the pharmacokinetics in whole blood following a single oral administration at 5 mg/kg bw demonstrated a rapid absorption and excretion of the test substance. The maximum concentration of total radioactivity (Cmax) observed occurred 8 h after administration in both sexes. The levels of radioactivity in blood decreased significantly by 48 h, consistent with rapid excretion. The terminal elimination phase half-life of female animals was considerably higher (114 h) than of male animals (48 h). This was reflected in the levels of radioactivity in female whole blood at 168 h, which were about 2-fold higher than in male animals.
In the 1000 mg/kg bw group, the investigation of whole blood pharmacokinetics revealed much slower absorption and excretion than that seen at the low dose level. The maximum concentration of total radioactivity was observed at 48 h post dosing, with concentrations after this declining rapidly at first, then more slowly after 96 h. The terminal elimination half-lifes for male and female animals were similar and consistent with low dose male animals, indicating that there was no effect of dose upon the terminal elimination phase half-lifes. Both AUC values measured for male and female animals were 22 - 28 times higher than at the low dose level. This was in comparison to an increase in 200-fold dose level, indicating non-dose linearity and a saturation of the absorption pathways at the high dose level.
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 21 Oct 1997 - 04 Mar 1999
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Objective of study:
- distribution
- 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)
- Version / remarks:
- Adopted in 1984
- 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
- Radiolabelling:
- yes
- Remarks:
- 14C radiolabelled test substance
- 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: males: 209 - 240 g, females: 151 - 190 g
- Housing: During acclimatisation, animals were housed up to 2 per cage in polypropylene and stainless steel cages with wood shavings as bedding. Following dose administration, the animals were housed individually 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, Witham, UK), ad libitum
- Water: tap water in drinking water quality, ad libitum
- Acclimation period: at least 7 days
ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 21 Oct 1997 To: 04 Mar 1999 - 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 days storage at +4 °C. The purity of a high dose level formulation was also shown to be 100% following 18 days storage. - Duration and frequency of treatment / exposure:
- single oral administration
- Dose / conc.:
- 5 mg/kg bw (total dose)
- Remarks:
- single treatment (gavage of the radiolabelled test substance)
- Dose / conc.:
- 1 000 mg/kg bw (total dose)
- Remarks:
- single treatment (gavage of the radiolabelled test substance)
- No. of animals per sex per dose / concentration:
- 12
- Control animals:
- no
- Positive control reference chemical:
- no
- Details on dosing and sampling:
- PHARMACOKINETIC STUDY (distribution)
- Tissues and body fluids sampled: 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, and residual carcass
- Time and frequency of sampling: 4 animals per sex of the 5 mg/kg bw group were sacrificed at 8, 24, and 48 h after administration and 4 animals per sex of the 1000 mg/kg bw group were sacrificed at 48, 72, and 96 h after administration (the chosen timepoints corresponded approximately to Cmax, Cmax/2 and Cmax/4 as determined in the pharmacokinetic experiment) - Type:
- distribution
- Results:
- highest levels of radioactivity detected for both dose groups in livers, kidneys, adrenals, pancreas and thyroid; peak concentrations in all tissues at the first sampling time (8 h (low dose) and 48 h (high dose), respectively)
- Details on distribution in tissues:
- 5 mg/kg bw:
At 8 h post dose, the distribution of total radioactivity was widespread and followed a similar pattern in the tissues from male and female rats. The highest concentrations of total radioactivity were observed in the liver and renal fat with mean concentrations of 14.485 and 11.713 µg equiv./g tissue in males and 13.291 and 11.418 µg equiv./g tissue in females, respectively. High concentrations were also observed in the adrenal gland, pancreas, kidney, thyroid gland and lungs with means of 9.805 to 4.249 µg equiv./g tissue in males and females, respectively (Table 1). In the ovaries from all female rats, also high concentrations of radioactivity (mean 5.228 µg equiv./g tissue) were observed. However, concentrations of radioactivity within the testes were lower (mean 2.376 µg equiv./g tissue). Of the remaining tissues, concentrations were similar to or below the observed plasma values with means of 4.099 and 2.454 µg equiv./g tissue in male and female rats, respectively.
High levels of radioactivity were observed in the contents of the gastrointestinal tract accounting for means of 30.2% (males) and 24.2% (females) of the administered radioactivity (Table 2). The levels of radioactivity within the contents of the stomach were lower with means of 2.97% (males) and 5.54% (females) of the radioactivity recovered. High amounts of radioactivity were present in the carcass, with means of 34.2% and 35.2% of the dose observed in males and females, respectively.
At 24 h post dosing, levels of radioactivity had decreased rapidly in all tissues (Table 1). The highest concentration was in the liver, where mean concentrations of 5.304 µg equiv./g tissue (males) and 3.172 µg equiv./g tissue (females) were observed. Concentrations within the kidney, renal fat, lungs, adrenal gland, pancreas, and thyroid gland had decreased to means of 1.633 to 0.709 µg equiv./g tissue in males and females, respectively. Concentrations in all other tissues, were below that observed in plasma (means of 2.311 and 0.806 µg equiv./g tissue in males and females, respectively).
Lower levels of radioactivity were also observed in the gastrointestinal tract and contents, with mean levels accounting for 16.7% and 13.5% of the radioactivity administered to males and females, respectively (Table 2). The amounts of radioactivity present in the stomach and contents were similar to those observed at 8 h post dosing (means of 3.05% and 2.00% in males and females, respectively). Within the carcass, levels of radioactivity had decreased to means of 6.70% in males and 5.53% in females.
At 48 h post dosing, concentrations of total radioactivity had decreased considerably in all tissues in both the male and female rats (Table 1). Within the liver, concentrations had decreased to means of 1.608 and 0.773 µg equiv./g tissue in males and females, respectively. All other tissues contained concentrations which were similar to or below that observed in plasma (means of 0.805 µg equiv./g tissue in males and 0.296 µg equiv./g tissue in females). Levels of radioactivity within the gastrointestinal tract and stomach had decreased to means of 4.60% and 1.12% of the administered dose in males and 3.24% and 0.34% in females, respectively (Table 2). Levels of radioactivity present in the carcass accounted for means of 1.84% and 2.28% of the dose in male and female animals, respectively.
1000 mg/kg bw:
High concentrations of total radioactivity were observed throughout the tissues of the male and female rats sacrificed at 48 h post dosing (Table 3). The highest concentrations of total radioactivity in male rats were observed in the renal fat, liver and adrenal gland with mean concentrations of 208.1, 160.5 and 119.7 µg equiv./g tissue, respectively. A high mean concentration was also observed in the thyroid gland (192.0 µg equiv./g tissue). However, this value may be artificially high, resulting from one outlying value (568.0 µg equiv./g tissue for 1/4 animals). Concentrations of radioactivity in the remaining animals were within the range of 61.0 - 73.8 µg equiv./g tissue (mean 66.6 µg equiv./g tissue). Lower concentrations of radioactivity were observed in the pancreas and kidneys (92.9 and 65.6 µg equiv./g tissue, respectively). The remaining tissues all contained concentrations which were similar to or below the level observed in plasma (63.3 µg equiv./g tissue). The tissue distribution pattern was similar in female rats, with the highest concentrations of radioactivity located within the renal fat, liver and adrenal gland (means of 138.0, 137.9, and 122.7 µg equiv./g tissue, respectively). Of the remaining tissues, only the bone marrow, muscle, spleen and whole blood contained concentrations which were below that in plasma (39.9 µg equiv./g tissue).
High levels of radioactivity were present in both the gastrointestinal tract and stomach of males, where mean concentrations of 14.2% and 10.4% of the administered dose were observed, respectively (Table 4). Only a small proportion of radioactivity (5.74%) remained in the carcass at this time, although this was slightly higher in the case of one animal, where approximately 12% of the administered radioactivity remained associated with the residual carcass. In females, 7.91% of the dose was recovered in the gastrointestinal tract and contents, compared to 24.5% in the stomach and contents. Levels of radioactivity present within the carcass of females were low, accounting for a mean of 2.48% of the administered radioactivity.
At 72 h post dosing, the concentrations of radioactivity had declined rapidly in all tissues in male rats (Table 3). The highest concentrations of radioactivity were present in the liver and renal fat where mean concentrations of 45.3 and 30.4 µg equiv./g tissue, respectively, were observed. Within all other tissues, the concentrations of radioactivity had decreased to levels which were below concentrations in plasma (mean 22.6 µg equiv./g tissue). The decrease in levels of radioactivity was more gradual in the tissues collected from female rats at 72 h post dosing. High mean concentrations were observed for a number of tissues such as renal fat (115.4 µg equiv./g tissue), liver (111.7 µg equiv./g tissue) and adrenal gland (87.7 µg equiv./g tissue). Lower concentrations of radioactivity were present in the ovaries, pancreas, kidneys, thyroid gland, lungs and heart (means of 56.7 - 33.9 µg equiv./g tissue). The remaining tissues contained concentrations which were similar to or below the mean concentration observed in plasma (30.1 µg equiv./g tissue).
The amounts of radioactivity contained in the contents of both the gastrointestinal tract and stomach had decreased to means of only 1.76% and 0.93% of the administered dose, respectively (Table 4). Less than 1.1% of the dose remained associated with the residual carcass. In the gastrointestinal tract and stomach of female rats, moderate amounts of radioactivity were present with means of 6.39% and 4.71% of the administered dose, respectively. Radioactivity remaining in the carcass accounted for less than 2.3% of the administered dose for all animals.
At 96 h post dosing, concentrations of radioactivity had declined to levels which were close to the limit of reliable determination for many tissues from male rats (Table 3). In male rats, the highest concentrations were observed in the liver, and skin and fur (means of 14.5 and 11.8 µg equiv./g tissue, respectively). In females, the concentrations for individual tissues remained higher than in males, with the highest concentrations observed in the liver, renal fat, adrenal gland and ovaries (means of 56.3, 30.7, 27.6 and 27.5 µg equiv./g tissue, respectively). Lower concentrations were present in the pancreas, thyroid gland, kidneys and lungs (23.7 - 16.2 µg equiv./g tissue, respectively). Concentrations of radioactivity in all other tissues were similar to, or below plasma (mean 14.1 µg equiv./g tissue).
Only small amounts of radioactivity were present in the gastrointestinal tract (means of 0.68% in males and 1.80% in females of the dose administered) and stomach (means of 0.04% in males and 1.06% in females of the dose administered) (Table 4). The levels of radioactivity remaining in the carcass were low, accounting for a mean of 0.23% of the dose in males and 0.60% of the dose in females. - Metabolites identified:
- not measured
- Conclusions:
- The results demonstrate a similar distribution of total radioactivity to male and female rats and show no retention of residues in a particular tissue.
Table 1: Concentration of total radioactivity in tissues following a single oral administration of 5 mg/kg bw test substance
Sample |
radioactivity [µg equiv./g tissue] |
|||||
8 h |
24 h |
48 h |
||||
males |
females |
males |
females |
males |
females |
|
Adrenals |
7.919 |
9.805 |
0.986 |
1.123* |
0.138 |
0.312 |
Bone marrow |
1.509 |
1.704 |
0.0364 |
0.314 |
0.086 |
0.78 |
Brain |
1.612 |
2.012 |
0.194 |
0.186 |
0.032 |
0.056 |
Renal fat |
11.713 |
11.418 |
1.472 |
1.623 |
0.153 |
0.371 |
Heart |
3.809 |
3.918 |
0.839 |
0.665 |
0.220 |
0.230 |
Kidneys |
5.364 |
5.867 |
1.633 |
1.151 |
0.496 |
0.328 |
Liver |
14.485 |
13.291 |
5.304 |
3.172 |
1.608 |
0.773 |
Lungs |
4.249 |
4.454 |
1.035 |
0.689 |
0.298 |
0.255 |
Muscle |
2.600 |
3.165 |
0.472 |
0.403 |
0.079 |
0.117 |
Pancreas |
6.429 |
7.559 |
0.949 |
0.897 |
0.150 |
0.265 |
Skin and fur |
4.412 |
3.520 |
0.714 |
0.722 |
0.242 |
0.261 |
Spleen |
2.384 |
2.418* |
0.423 |
0.401 |
0.097 |
0.156 |
Testes/Ovaries |
2.376 |
5.228 |
0.563 |
0.707 |
0.132 |
0.196 |
Thyroid |
5.316 |
5.854 |
0.884 |
24.9 |
0.250 |
0.223 |
Whole blood |
2.211 |
1.525 |
1.379 |
0.723 |
0.564 |
0.428 |
Plasma |
4.099 |
2.454 |
2.311 |
0.806 |
0.805 |
0.296 |
Table 2: Amounts of total radioactivity in tissues following a single oral administration of 5 mg/kg bw test substance
Sample |
radioactivity [% of administered dose] |
|||||
8 h |
24 h |
48 h |
||||
males |
females |
males |
females |
males |
females |
|
Adrenals |
0.03 |
0.05 |
0.00 |
0.01* |
0.00* |
0.00 |
Brain |
0.27 |
0.39 |
0.03 |
0.04 |
0.01 |
0.01 |
Heart |
0.30 |
0.37 |
0.07 |
0.06 |
0.02 |
0.02 |
Kidneys |
0.97 |
1.12 |
0.30 |
0.23 |
0.10 |
0.07 |
Liver |
12.2 |
11.0 |
5.52 |
3.38 |
1.76 |
0.83 |
Lungs |
0.46 |
0.55 |
0.13 |
0.10 |
0.04 |
0.03 |
Pancreas |
0.27 |
0.32 |
0.03 |
0.04 |
0.01 |
0.01 |
Spleen |
0.13 |
0.12* |
0.02 |
0.02 |
0.01 |
0.01 |
Testes/Ovaries |
0.57 |
0.03 |
0.14 |
0.01 |
0.03 |
0.00 |
Thyroid |
0.01 |
0.01 |
0.00 |
0.00 |
0.00 |
0.00 |
GI tract and contents |
30.2 |
24.2 |
16.7 |
13.5 |
4.60 |
3.24 |
Stomach and contents |
2.97 |
5.54 |
3.05 |
2.00 |
1.12 |
0.34 |
Carcass |
34.2 |
35.2 |
6.70 |
5.53 |
1.84 |
2.28 |
Total |
82.5 |
78.9 |
32.7 |
24.9 |
9.52 |
6.85 |
Table 3: Concentration of total radioactivity in tissues following a single oral administration of 1000 mg/kg bw test substance
Sample |
radioactivity [µg equiv./g tissue] |
|||||
48 h |
72 h |
96 h |
||||
males |
females |
males |
females |
males |
females |
|
Adrenals |
119.7 |
122.7 |
17.5* |
87.7 |
4.5* |
27.6 |
Bone marrow |
23.6 |
18.5 |
4.0 |
22.0 |
1.6* |
7.1 |
Brain |
24.8 |
68.4 |
4.2* |
20.7 |
1.0* |
6.8 |
Renal fat |
208.1 |
138.0 |
30.4 |
115.4 |
6.9 |
30.7 |
Heart |
49.8 |
46.4 |
10.6 |
33.9 |
3.0 |
14.1 |
Kidneys |
65.6 |
63.4 |
20.1 |
47.4 |
7.3 |
19.7 |
Liver |
160.5 |
137.9 |
45.3 |
111.7 |
14.5 |
56.3 |
Lungs |
55.7 |
49.0 |
15.0 |
37.3 |
4.3 |
16.2 |
Muscle |
31.7 |
33.6 |
6.4 |
22.7 |
1.6* |
6.9 |
Pancreas |
92.9 |
86.1 |
15.6 |
56.5 |
3.8* |
23.7 |
Skin and fur |
45.2 |
37.5 |
12.5 |
30.3 |
11.8 |
13.1 |
Spleen |
32.1 |
31.4 |
5.0* |
25.3 |
1.8 |
9.3 |
Testes/Ovaries |
36.7 |
63.8 |
8.3 |
56.7 |
2.1 |
27.5 |
Thyroid |
192.0 |
64.6 |
16.7 |
43.8 |
5.2* |
20.0 |
Whole blood |
50.7 |
28.9 |
13.3 |
21.8 |
5.1 |
9.6 |
Plasma |
63.3 |
39.9 |
22.6 |
30.1 |
7.9 |
14.1 |
Table 4: Amounts of total radioactivity in tissues following a single oral administration of 1000 mg/kg bw test substance
Sample |
radioactivity [% of administered dose] |
|||||
48 h |
72 h |
96 h |
||||
males |
females |
males |
females |
males |
females |
|
Adrenals |
0.00 |
0.00 |
0.00* |
0.00 |
0.00* |
0.00 |
Brain |
0.02 |
0.06 |
0.00* |
0.02 |
0.00* |
0.01 |
Heart |
0.02 |
0.02 |
0.00 |
0.01 |
0.00 |
0.01 |
Kidneys |
0.06 |
0.06 |
0.02 |
0.04 |
0.01 |
0.02 |
Liver |
0.96 |
0.88 |
0.33 |
0.81 |
0.12 |
0.44 |
Lungs |
0.03 |
0.03 |
0.01 |
0.02 |
0.00 |
0.01 |
Pancreas |
0.02 |
0.02 |
0.00 |
0.01 |
0.00* |
0.01 |
Spleen |
0.01 |
0.01 |
0.00* |
0.00 |
0.00 |
0.00 |
Testes/Ovaries |
0.05 |
0.00 |
0.01 |
0.00 |
0.00 |
0.00 |
Thyroid |
0.00 |
0.00 |
0.00 |
0.00 |
0.00* |
0.00 |
GI tract and contents |
14.2 |
7.91 |
1.76 |
6.39 |
0.68 |
1.80 |
Stomach and contents |
10.4 |
24.5 |
0.93 |
4.71 |
0.04 |
1.06 |
Carcass |
5.74 |
2.48 |
0.58 |
1.54 |
0.23 |
0.60 |
Total |
31.5 |
36.0 |
3.20 |
13.6 |
1.08 |
3.95 |
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 21 Oct 1997 - 04 Mar 1999
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Objective of study:
- absorption
- excretion
- metabolism
- 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)
- Version / remarks:
- Adopted in 1984
- 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
- Radiolabelling:
- yes
- Remarks:
- 14C radiolabelled test substance
- 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: males: 295 - 355 g, females: 244 - 292 g
- Housing: During acclimatisation, animals were housed up to 2 per cage in polypropylene and stainless steel cages with wood shavings as bedding. Following dose administration, the animals were housed individually 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, Witham, UK), ad libitum
- Water: tap water in drinking water quality, ad libitum
- Acclimation period: at least 7 days
ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 21 Oct 1997 To: 04 Mar 1999 - 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.
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 days storage at +4 °C. The purity of a high dose level formulation was also shown to be 100% following 18 days storage. - Duration and frequency of treatment / exposure:
- single oral administration
- Dose / conc.:
- 5 mg/kg bw (total dose)
- Remarks:
- single treatment (gavage of the radiolabelled test substance)
- Dose / conc.:
- 1 000 mg/kg bw (total dose)
- Remarks:
- single treatment (gavage of the radiolabelled test substance)
- No. of animals per sex per dose / concentration:
- 8 animals/sex/dose were subjected to surgery
only the results of 5 animals/sex/dose (survivors) were reported - Control animals:
- no
- Positive control reference chemical:
- no
- Details on dosing and sampling:
- PHARMACOKINETIC STUDY (absorption, excretion)
- Tissues and body fluids sampled: urine, faeces, bile, and cage wash
- Time and frequency of sampling: urine and bile at 6, 12, 24, 48, 72, and 96 h post dosing; faeces and cage wash at 12, 24, 48, 72, and 96 h post dosing
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces, and bile
- Time and frequency of sampling: 0 - 72 h post-dose
- From how many animals: 5 animals (pooled per sex and dose)
- Method type(s) for identification: HPLC-MS, radio-HPLC - Type:
- absorption
- Results:
- 5 mg/kg bw: extensive and rapid absorption regarding the low excretion via faeces (10.5% of the dose in males and females); 1000 mg/kg bw: low absorption regarding the high excretion via faeces (86.0% and 79.3% of the dose in males and females)
- Type:
- metabolism
- Results:
- 5 mg/kg bw: extensive metabolism, wide metabolite pattern in urine and bile; 1000 mg/kg bw: extensive metabolism, wide metabolite pattern in urine and bile but majority of the test substance found unmetabolized in faeces
- Type:
- excretion
- Results:
- 5 mg/kg bw: major route of excretion within 96 h via bile (males: 67.2% of the dose, females: 51.6% of the dose); 1000 mg/kg bw: major route of excretion within 96 h via faeces (males: 86.0% of the dose, females: 79.3% of the dose)
- Details on absorption:
- 5 mg/kg bw:
The absorption of the administered dose was extensive and rapid. Regarding the low excretion via faeces (10.5% of the dose in males and females), at least about 89% of an oral dose of the radiolabelled test substance at the low dose level was absorbed, with the bulk of this absorbed within 24 h post dosing.
1000 mg/kg bw:
The absorption of the administered dose was low. Excretion via faeces (86.0% (males) and 79.3% (females)) indicated that it was likely that only about 14% (males) and 20% (females) of an oral dose of the radiolabelled test substance at the high dose level was absorbed. - Details on excretion:
- 5 mg/kg bw:
Following administration, the major route of excretion was via bile, with mean values of 67.2% and 51.6% of the dose recovered by 96 h post dosing for males and females, respectively. Excretion via urine and faeces over the same period accounted for 11.0% and 10.5% of the administered dose in males and 30.4% and 10.5% of the administered dose in females, respectively. Excretion was rapid, with mean recoveries (in bile, urine, faeces and cage wash) of 35.2%, 68.5%, and 88.3% of the administered dose recovered by 12, 24 and 48 h post dosing, respectively, in males. The rate of recovery in female rats was similar to males with mean recoveries of 27.1%, 51.3%, and 80.2% of the administered dose recovered by 12, 24, and 48 h post dosing, respectively. By the end of the study period at 96 h post dosing the mean recovery of total radioactivity from bile, urine, faeces and cage wash accounted for 92.4% and 95.6% of the dose in males and females, respectively. Recovery of total radioactivity from the remaining carcasses was low, accounting for mean values of 1.49% and 3.49% of the dose in males and females, respectively, suggesting low residues remained in the tissues. Recovery in all samples by the end of the study period represented mean values of 93.9% and 99.1% of the administered dose in males and females, respectively.
1000 mg/kg bw:
Following administration, the major route of excretion was via faeces with a mean value of 86.0% and 79.3% of the dose recovered by 96 h post dosing for males and females, respectively. Excretion via urine and bile over 96 h accounted for 1.1% and 8.9% of the administered dose in males and 1.5% and 7.0% of the administered dose in females. Excretion was rapid with mean recoveries (in bile, urine, faeces and cage wash) of 60.3%, 82.2%, and 92.3% of the administered dose by 24, 48, and 72 h post dosing, respectively, in males. The rate of recovery in females rats was similar to males with mean recoveries of 40.6%, 64.0%, and 77.5% of the administered dose recovered by 24, 48, and 72 h post dosing, respectively. By the end of the study period at 96 h post dosing the mean recovery of total radioactivity from bile, urine, faeces and cage wash accounted for 96.5% and 87.8% of the dose in males and females, respectively. Recovery of total radioactivity from the remaining carcasses was low, accounting for mean values of 0.36% and 5.78% of the dose in males and females, respectively, suggesting low residues remained in the tissues. Recovery in all samples by the end of the study period represented mean values of 96.9% and 93.6% of the administered dose in males and females, respectively. - Metabolites identified:
- yes
- Details on metabolites:
- 5 mg/kg bw:
The radio-HPLC profile was obtained from 0 - 72 h pooled urine, faeces and bile from bile duct cannulated male and female rats dosed at the low dose level. The profile in urine included a wide range of polar components that indicate an extensive metabolism (Table 1 under "Any other information on results incl. tables"). 5 components co-chromatographed with the supplied reference standards RPA 112705, RPA 114345, RPA 104615, MB 45897 and RPA 97973 in males and females. Additionally, RPA 112716 and RPA 112917 were also observed but only in females. 6 further significant metabolites were observed, and based on similarity of retention time and pattern of occurrence, these were identified as U1, U2, U4, U5, U6, and U7. In the urine of females, U7 was not observed. A further 4 polar, unknown components, ranging between 0.12% and 0.26% of the dose, were detected in males. The major urinary metabolite in cannulated male and female rats was the component U2 (4.81 and 10.6% of dose in males and females, respectively).
In faeces, the radio-HPLC profile revealed the presence of 5 metabolites (Table 2 under "Any other information on results incl. tables"). These components co-chromatographed with RPA 114345, MB 45897, RPA 97973, RPA 107566 and the parent component, respectively. The major metabolites in faeces of cannulated male and female rats were RPA 114345 (2.94 and 3.29% of administered dose in males and females, respectively) and RPA 97973 (2.35 and 4.54% of administered dose in males and females, respectively).
In bile, the radio-HPLC profile showed an extensive pattern of metabolites (13 in males and 14 in females) covering a wide range of polarities (Table 3). Of the metabolites detected, 7 co-chromatographed with RPA 112705, RPA 114345, RPA 97973, RPA 112716, RPA 112916, RPA 104615 and MB 45897. The component which co-chromatographed with RPA 97973 was not detected in males and the component MB 45897 seen in male bile was not detected in females. The remaining metabolites were named B4, B5, B6, B1, B2, B7 and B8. It was considered possible that some of these components, B1, B2, B3 and B7 may have been the same components as U1, U2, U3 and U7, but it was not possible to tell definitively by HPLC analysis. In general, the abundance of each metabolite in female bile was lower than in male bile, reflecting the lower excretion of total radioactivity in female bile. The major biliary metabolites were B1 (10.66 and 9.16% of administered dose in males and females, respectively) and B3 (15.70 and 11.44% of administered dose in males and females, respectively).
1000 mg/kg bw:
The radio-HPLC profile was obtained from 0 - 72 h pooled urine, faeces and bile from bile duct cannulated male and female rats dosed at the high dose level. The profile in urine revealed 8 and 10 metabolites in males and females, respectively, which covered a wide range of polarities (Table 1 under "Any other information on results incl. tables"). Four components were identified as RPA 112705, RPA 114345, RPA 104615 and MB 45897, respectively. Furthermore, the parent compound and RPA 97973 were detected only in male urine. The polar metabolites U1 and U2 were detected in both sexes and U8 and U6 were observed only in female urine. The major urinary metabolite in cannulated male and female rats was the component MB 45897 (0.29 and 0.34% of administered dose in males and females, respectively).
In faeces, the parent compound was the major component, accounting for 76.35 and 62.94% of administered dose in males and females, respectively (Table 2 under "Any other information on results incl. tables"). Smaller quantities of RPA 97973 in male faeces and RPA 107566 in male and female faeces were also observed.
The radio-HPLC profile of pooled 0 - 72 h bile from high dose male and female rats was qualitatively similar to that observed for the low dose rats. 17 metabolites were observed in males and 16 in females (Table 3 under "Any other information on results incl. tables"). Of these metabolites, 4 were identified as RPA 112705, RPA 112716, RPA 104615 and MB 45897. In females, additionally the metabolite RPA 97973 was detected. The components B4, B5, B6, B1, B2 and B7 were observed in males and females and B8 in males only. 5 unknown metabolites were observed in females and 6 in males. The major biliary metabolites were B1 (1.75 and 0.94% of administered dose in males and females, respectively) and B2 (1.68 and 1.00% of administered dose in males and females, respectively). - Conclusions:
- The results demonstrated different routes of excretion after administration of 5 and 1000 mg/kg bw of the test substance. Based on the low excretion via faeces (about 10% of the administered dose in males and females), the low dose of the test substance was absorbed extensively and rapidly. The major route of excretion within 96 h was via bile (67.2 and 51.6% of the dose for males and females, respectively). In the high dose group, the major route of excretion within 96 h was via faeces (86.0% and 79.3% of the dose for males and females, respectively), indicating that only 14% (males) and 20% (females) of an oral dose of the radiolabelled test substance at the high dose level were absorbed. Only a minor part of the test substance was excreted via bile (8.9% and 7.0% of the dose in males and females, respectively).
After 96 h, the mean recovery of total radioactivity from bile, urine, faeces and cage wash was similar in the low and high dose groups.
The metabolite pattern in urine and bile of both 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 low dose group 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.
Table 1: Quantitative distribution of radioactivity following radio-HPLC analysis of pooled urine sample of male and female rats (0 - 72 h)
Component |
individual components as % of dose |
|||
5 mg/kg bw |
1000 mg/kg bw |
|||
males |
females |
males |
females |
|
parent component |
--- |
--- |
0.05 |
--- |
RPA 112705 |
0.48 |
5.23 |
0.05 |
0.18 |
RPA 114345 |
0.71 |
1.84 |
0.06 |
0.04 |
RPA 97973 |
0.12 |
0.57 |
0.04 |
--- |
RPA 112716 |
--- |
0.31 |
--- |
--- |
RPA 112917 |
--- |
0.33 |
--- |
--- |
RPA 104615 |
0.81 |
2.18 |
0.12 |
0.10 |
MB 45897 |
0.35 |
2.84 |
0.29 |
0.34 |
U1 |
0.72 |
1.93 |
0.07 |
0.10 |
U2 |
4.81 |
10.60 |
0.27 |
0.03 |
U4 |
0.79 |
0.89 |
--- |
--- |
U5 |
0.29 |
0.57 |
--- |
--- |
U6 |
0.46 |
1.25 |
--- |
0.04 |
U7 |
0.23 |
--- |
--- |
--- |
U8 |
--- |
--- |
--- |
0.04 |
unknown (sum) |
0.83 |
--- |
--- |
0.05 |
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 pooled faeces sample of male and female rats (0 - 72 h)
Component |
individual components as % of dose |
|||
5 mg/kg bw |
1000 mg/kg bw |
|||
males |
females |
males |
females |
|
parent component |
1.53 |
0.44 |
76.35 |
62.94 |
RPA 114345 |
2.94 |
3.29 |
--- |
--- |
RPA 97973 |
2.35 |
4.54 |
0.63 |
--- |
RPA 107566 |
2.25 |
2.05 |
4.73 |
2.54 |
MB 45897 |
0.51 |
0.37 |
--- |
--- |
unknown (sum) |
--- |
--- |
--- |
--- |
Table 3: Quantitative distribution of radioactivity following radio-HPLC analysis of pooled bile sample of male and female rats (0 - 72 h)
Component |
individual components as % of dose |
|||
5 mg/kg bw |
1000 mg/kg bw |
|||
males |
females |
males |
females |
|
RPA 112705 |
6.63 |
2.55 |
0.67 |
0.30 |
RPA 112716 |
0.91 |
1.34 |
0.15 |
0.47 |
RPA 112916 |
1.93 |
1.03 |
--- |
--- |
RPA 114345 |
6.38 |
3.37 |
--- |
--- |
RPA 104615 |
15.70 |
11.44 |
0.58 |
0.45 |
RPA 97973 |
--- |
0.62 |
--- |
0.06 |
MB 45897 |
0.89 |
--- |
0.15 |
0.08 |
B1 |
10.66 |
9.16 |
1.75 |
0.94 |
B2 |
8.41 |
8.21 |
1.68 |
1.00 |
B4 |
1.29 |
1.70 |
0.90 |
0.40 |
B5 |
6.68 |
4.73 |
0.58 |
0.42 |
B6 |
3.94 |
2.38 |
0.29 |
0.17 |
B7 |
2.06 |
0.96 |
0.34 |
0.10 |
B8 |
1.21 |
0.98 |
0.05 |
--- |
unknown (other, sum) |
--- |
1.43 |
0.67 |
0.56 |
B1: Unknown
B2: Unknown
B4: Unknown
B5: Unknown
B6: Unknown
B7: Unknown
B8: Unknown
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 999
- 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)
- Version / remarks:
- Adopted in 1984
- 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
- 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
Constituent 1
- Radiolabelling:
- yes
- Remarks:
- 14C radiolabelled test substance
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: males: 206 - 242 g, females: 166 - 193 g
- Housing: During acclimatisation, animals were housed up to 2 per cage in polypropylene and stainless steel cages with wood shavings as bedding. Following dose administration, animals used in excretion collections were individually housed in glass metabolism cages designed for the separate collection of urine and faeces. All other animals were housed in individual propylene and stainless steel cages with raised wire mesh floors to inhibit coprophagy.
- Individual metabolism cages: yes
- Diet: SDS Rat and Mouse Maintenance Diet No. 1 (Special Diet Services, Witham, UK), ad libitum
- Water: tap water in drinking water quality, ad libitum
- Acclimation period: at least 7 days
ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 21 Oct 1997 To: 04 Mar 1999
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 days storage at +4 °C. The purity of a high dose level formulation was also shown to be 100% following 18 days storage. - Duration and frequency of treatment / exposure:
- 5 and 1000 mg/kg bw: single oral administration
5 mg/kg bw/day: daily for 15 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 5 mg/kg bw (total dose)
- Remarks:
- single treatment (gavage of the radiolabelled test substance)
- Dose / conc.:
- 1 000 mg/kg bw (total dose)
- Remarks:
- single treatment (gavage of the radiolabelled test substance)
- Dose / conc.:
- 5 mg/kg bw/day
- Remarks:
- treatment for 15 days (daily gavage of the non-labelled test substance for 14 days, followed by a single gavage administration of the radiolabelled test substance on Day 15), only for main absorption, distribution, metabolism and excretion experiments
- 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, and residual carcass)
- Time and frequency of sampling: urine at 6, 12, 24, 48, 72, 96, 120, 144 and 168 h post radioactive dosing; faeces and cage washes at 12, 24, 48, 72, 96, 120, 144 and 168 h post radioactive dosing; tissues at 168 h post radioactive dosing
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 days. Expired air was collected daily into 2 serial traps containing 2-ethoxyethanol:ethanolamine (7:3, v/v) for 2 days. 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 dosing. 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 (GI) 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/day following 14 day oral administration of non-radiolabelled test substance and 1 day oral administration of radiolabelled test substance at a target dose level of 5 mg/kg bw/day:
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 tissue), respectively. In plasma and whole blood of males, concentrations of 0.036 and 0.041 µg equiv./g tissue 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 tissue), respectively. In plasma and whole blood of females, concentrations of 0.027 and 0.266 µg equiv./g tissue 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 tissue, respectively). In plasma, concentrations of radioactivity of 1.2 µg equiv./g tissue 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 tissue, respectively). In plasma, concentrations of radioactivity of 0.5 µg equiv./g tissue 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/day following 14 day oral administration of non-radiolabelled test substance and 1 day oral administration of radiolabelled test substance at a target dose level of 5 mg/kg bw/day:
Following sacrifice of the animals at 168 h post radiolabelled dosing, 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 tissue (males) and 0.32 µg equiv./g tissue (females). Concentrations in all other tissues collected were similar to those present in plasma (0.09 and 0.03 µg equiv./g tissue for males and females, respectively), with the exception of whole blood in female animals (0.195 µg equiv./g tissue).
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 dosing. 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 dosing. 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 dosing, 77.3% (males) and 64.0% (females) of the administered dose had been recovered, which increased by 72 h post dosing 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/day following 14 day oral administration of non-radiolabelled test substance and 1 day oral administration of radiolabelled test substance at a target dose level of 5 mg/kg bw/day:
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 bw/day 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 dosing. 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.
Based on study results, no bioaccumulation potential observed.
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). 10 - 12 significant metabolites were observed in male and female rats. 4 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 h timepoint and RPA 112705 was not detected until the 12 - 24 h timepoint. One major difference 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/day following 14 day oral administration of non-radiolabelled test substance and 1 day oral administration of radiolabelled test substance at a target dose level of 5 mg/kg bw/day:
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). 11 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 repeated 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 h post dosing. 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 |
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:
- 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/day 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 dosing, 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.
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