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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Cross-reference
Reason / purpose:
reference to other study
Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose:
reference to other study
Objective of study:
excretion
metabolism
Qualifier:
according to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Version / remarks:
23 July, 2010
GLP compliance:
yes
Specific details on test material used for the study:
14C-LABELED TEST SUBSTANCE
- Batch No.of test material: 1248-1101
- Purity (radiochemical): > 98%

RADIOLABELLING INFORMATION
- Radiochemical purity: >98 %
- Specific activity: 13.2 MBq/mg of AI, 59.6 MBq/mg in acetonitrile
- Locations of the label: phenyl-U-14C

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: freezer
- Solubility and stability of the test substance in the solvent/vehicle: A stability of the test substance in sodium carboxymethyl cellulose in drinking water with a comparable batch of the non-labeled test substance over a period of 7 days stored in the refrigerator is given.


13C-LABELED TEST SUBSTANCE
- Batch No.of test material: 1248-2101
- Purity (radiochemichal): 94.0%

RADIOLABELLING INFORMATION
- Radiochemical purity: 94.0%
- Locations of the label: phenyl-1,2,3,4,5,6,-13C
- Storage condition of test material: freezer


NON-LABELED TEST SUBSTANCE
- Batch No. of thest material: 03508136W0
- Content: 99.9 g/100 g
- Storage condition of test material: ambient (RT)
- Storage stability: 23 Nov 2019


TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: In order to achieve the required specific activity, respective aliquots of a solution of the radio-labeled test substance will be taken and the organic solvent will be evaporated to dryness. , Respective amounts of non-labeled test substance and, if foreseen 13C-labeled test substance, are added to the dried residue and filled up to the final volume with the aqueous vehicle (0.5% sodium carboxymethyl cellulose (CMC) in water). Due to the possibility to facilitate the structure elucidation of formed metabolites, 13C-test-substance will be added to the test substance preparation with 14C-test-substance for the balance experiments and for the bile excretion experiments. For these experiments, 13C-labeled test substance is mixed with non-labeled test substance in a ratio of 1 : 2 (w : w). In order to achieve the required specific activity, respective amounts of 14C-labeled test substance will be added. Each mixture will be filled up with the carrier to the final volume.

- Final dilution of a dissolved solid, stock liquid or gel: The test substance will be prepared in 0.5 % sodium carbodymethyl cellulose in tap water (CMC). 10 mL/kg bw of test substance preparation will be dosed orally by gavage.
Radiolabelling:
yes
Species:
rat
Strain:
Wistar
Remarks:
Crl:WI (Han)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, 97633 Sulzfeld, Germany
- Age at study initiation: 11-13 weeks
- Avarage Weight at study initiation:
VM: 325.09 g; VF: 192.52 g; WM: 326.66 g and WF: 191.48 g
- Housing:
Housing during acclimatication: Animals held in groups of four individuals in Makrolon cages (Type 4)
Housing during experiment: Animals individually placed in Makrolon cages (Type 3)
- Diet: Kliba 3433 (GLP Batch 04/18), ad libitum prior to and during the experiment
- Water: tap water, ad libitum
- Acclimatization at least 7 days before treatment

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 - 27 °C
- Humidity (%): 34 - 65 %
- Photoperiod (hrs dark / hrs light): 12 h / 12 h
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5 % in tap water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
For each dose group appropriate amounts of 14C-labelled, 13C-labelled and unlabelled DHDPS were weighed. The mixture was then mixed with 0.5% aqueous CMC to generate App0001 (dose groups VM and VF) and App0002 (dose groups WM and WF).
Duration and frequency of treatment / exposure:
Dosing was performed once orally with a mixture of 14C-labelled, 13C-labelled and unlabelled DHDPS by gavage. The test item preparations were applied at a nominal rate of 30 mg/kg bw (dose groups VM and VF) and 300 mg/kg bw (dose groups WM and WF).
For additional information please refer to "Any other information on materials ans methods incl. tables".
Dose / conc.:
30 mg/kg bw (total dose)
Remarks:
low dose
Dose / conc.:
300 mg/kg bw (total dose)
Remarks:
high dose
No. of animals per sex per dose:
see "Any other information on materials ans methods incl. tables"
Control animals:
no
Details on study design:
The generation of samples for dose groups BM, BF, DM, DF, CM, CF, RM, RF, SM and SF and the kinetic investigation were performed at the Department of Molecular Toxicology and Kinetics of BASF SE (RB/TB, Ludwigshafen) as a separated study (Project No. 02B0423/17B007). The in-life phase and the kinetic data for those animals are reported in detail in the corresponding study report.
For dose groups BM, BF, DM, DF, CM and CF urine was collected after 6 hours, 12 hours and 24 hours, and thereafter in intervals of 24 hours for up to 168 hours. Faeces of these groups were collected in intervals of 24 hours up to 168 hours. For dose groups RM, RF, SM and SF (bile excretion experiments), urine and faeces were collected after 24 hours and thereafter in intervals of 24 hours up to 72 hours. Bile was collected in time intervals of 3 hours up to 72 hours. After sacrifice, the cages of all animals were rinsed, and the cage wash was also radio-assayed for determination of the excretion balance.

Samples generated for radioactivity determination and metabolic profiling were shipped to BASF Agricultural Center Limburgerhof (Germany) of BASF SE, Crop Protection – Ecology and Environmental Analytics and analysed within the present excretion and metabolism study, which included also the in-life phase for the dose groups VM, VF, WM and WF.
For each of the dosing groups VM, VF, WM and WF four animals were dosed. Dosing was performed once orally with a mixture of 14C-labelled, 13C-labelled and unlabelled DHDPS by gavage. The test item preparations were applied at a nominal rate of 30 mg/kg bw (dose groups VM and VF) and 300 mg/kg bw (dose groups WM and WF).
The animals were sacrificed at or near the presumed maximum plasma generation at 1 hour. They were anesthetized with isoflurane and 1% lidocaine and killed by exsanguination. Liver, kidney, blood, plasma and carcass were sampled for dose groups VM, VF, WM and WF.

For additional information please refer to "Any other information on materials ans methods incl. tables".
Type:
metabolism
Results:
identification of parent compund, glucuronidated metabolite, sulphated metabolite, glucuronidated and sulphated metabolite
Type:
excretion
Results:
mostly completed within 48-72 h; excretion via urin: 48-56% of dose; excretion via faeces: 41-44% of dose
Details on excretion:
BALANCE/EXCRETION:
HIGH DOSE (300 mg/kg bw) (experiment 3):
Mean total recoveries of radioactivity:Male rats 95.14% and 98.58 % in female rats, respectively.
The urinary excretion occurred predominantly within 48 hours after exposure. Within 48 hours after single oral administration of 300 mg/kg bw to male and female rats 41.30 and 34.00 % of the administered radioactivity were found in urine, respectively. After 168 hours the total urinary excretion of radioactivity was 48.05 and 39.02 % of dose for males and females, respectively.
38.74 % (males) and 50.13 % (females) of the administered radioactivity were excreted within the first 48 hours via feces. After 168 hours the total amount of radioactivity excreted via feces was found to be 44.20 and 55.71 % of dose
for males and females, repectively.
Major excretion of absorbed 14C-4,4'-sulphonyldiphenol occurs within 48 hours after dosing. Together with cage wash, the total amount of excreted radioactivity was found to be 94.81 % of the administered radioactivity in males and 97.33 % of the administered radioactivity in females reflecting more or less complete excretion of orally dosed 14C-4,4'-sulphonyldiphenol for male and femalte rats. 168 hours post-dosing, small amounts with contents ranging from 0.01-1.16% of the dose of 14C-4,4'-sulphonyldiphenol were found in skin, carcass, gut and stomach contentand gut content for male and female animals.

LOW DOSE (30 mg/kg bw) (experiment 4):
Mean total recoveries of radioactivity: 105.33% (males) and 97.17 % (females). Negligible amounts (< 0.1% of the administered dose) were measured in exhaled air.
Excretion in urine within 48 hours after single oral administration contributed to 56.94% in male rats and 47.09% in female rats of the administered radioactivity. Total excretion of radioactivity via urine after 168 hours was 60.13 and 51.45 % of dose for males and females, respectively.
Urinary excretion predominantly takes place within 48 hours after test substance adminstration.
During the first 48 hours after administration, 41.75 % and 39.40 % of the administered radioactivity were excreted via feces by males and females, respectively. After 168 hours the total amount of radioactivity excreted via feces was found to be 43.00 and 40.85 % of dose
for males and females, repectively.
Also, fecal excretion occurs mainly within the first 2 days after administration of the substance.
Together with cage wash, the total amount of excreted radioactivity was found to be 104.33% of the administered radioactivity in males and 96.06 % of the administered radioactivity in females reflecting more or less complete excretion of orally dosed 14C-4,4'-sulphonyldiphenol
for male and female rats. 168 hours post-dosing, only traces of radioactive residues of 14C-4,4'-sulphonyldiphenol were found in carcass, skin, stomach content, gut content and gut. Highest total radioactive residues (in μg Eq/g) 168 h post dosing (except GI tract)
were found in carcass for both sexes, for all other tissues the residues ranged between 0.0
and 0.1 μg Eq/g.

EXPERIMENT 5 (14 days once daily non-labeled, radio-labeled once on day 15, 30 mg/kg bw):
Mean total recoveries of radioactivity were 96.21 and 99.69% of dose in male and female rats, respectively.
Predominantly excreted within 48 hours after administration via urine and feces. The balance data demonstrate that excretion of 14C-4,4'-sulphonyldiphenol dosed orally by gavage to Wistar rats at a single low and high dose as well as multiple low dose (14 + 1) was fast via urine and feces. Urinary excretion was slightly higher than fecal excretion for male animals of both dose groups and female animals of the low dose group, single and multiple dosing, whereas for female animals of the high dose group, excretion via urine was about 17 % lower than fecal excretion. Excretion was almost complete and occurred to a major extent within two days after oral dosing.
The excretion of 14C-4,4'-sulphonyldiphenol in the low dose is independent from frequency of treatment and gender.

EXCRETION VIA BILE
HIGH DOSE (300 mg/kg bw):
Mean total recoveries of radioactivity were 93.83 and 97.55% of dose in male and female rats, respectively.
Within 72 hours after administration: excretion via bile 43.81% (males) and 45.65% (females)

The bile excretion experiments show that excretion of 14C-4,4'-sulphonyldiphenol dosed orally by gavage to Wistar rats with single doses of 300 and 30 mg/kg bw was fast and occurred mainly via urine (HIGH DOSE: 47.52 (males) and 48.91% (females); LOW DOSE: 37.72 (males) and 46.37 % (females)) and via bile (HIGH DOSE: 43.81 (males) and 45.65 % (females); LOW DOSE: 56.39 (males) and 38.21 % (females) for both dose levels.
Compared to the balance experiments, mean urinary excretions were generally lower in bile excretion experiments, except for females of the high dose experiment, demonstrating reabsorption of the test substance into the systemic circulation under physiological conditions. This finding correlates to indications for potential enterohepatic recirculation obtained in plasmakinetic experiments.
Metabolites identified:
yes
Details on metabolites:
Metabolite patterns in urine:
Identification of three components in urine sampled within 0–72 h after dosing.
- glucuronidated metabolite was the main component in urine of all dose groups except for dose group DM, where it was the least abundant compound. 30.68–35.42% glucuronidated metabolite of the dose for the single and repeated low dose groups and 6.42–19.51% of the dose in the high dose groups.
- parent compound DHDPS was the second most abundant compound in urine, except for dose group DM, where it was the most abundant compound, and accounted for 7.48–24.14% of the dose.
The least abundant compound was

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019
Report Date:
2019

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Version / remarks:
23 July, 2010
Deviations:
no
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Specific details on test material used for the study:
14C-LABELED TEST SUBSTANCE
- Batch No.of test material: 1248-1101
- Expiration date of the lot/batch: 23 Nov 2019
- Purity (radiochemical): > 98%

RADIOLABELLING INFORMATION
- Radiochemical purity: >98 %
- Specific activity: 13.2 MBq/mg of AI, 59.6 MBq/mg in acetonitrile
- Locations of the label: phenyl-U-14C

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: freezer
- Solubility and stability of the test substance in the solvent/vehicle: A stability of the test substance in sodium carboxymethyl cellulose in drinking water with a comparable batch of the non-labeled test substance over a period of 7 days stored in the refrigerator is given.


13C-LABELED TEST SUBSTANCE
- Batch No.of test material: 1248-2101
- Purity (radiochemichal): >94%

RADIOLABELLING INFORMATION
- Radiochemical purity: >94%
- Locations of the label: phenyl-1,2,3,4,5,6,-13C
- Storage condition of test material: freezer


NON-LABELED TEST SUBSTANCE
- Batch No. of thest material: 03508136W0
- Content: 99.9 g/100 g
- Storage condition of test material: ambient (RT)
- Storage stability: 23 Nov 2019


TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: In order to achieve the required specific activity, respective aliquots of a solution of the radio-labeled test substance will be taken and the organic solvent will be evaporated to dryness. , Respective amounts of non-labeled test substance and, if foreseen 13C-labeled test substance, are added to the dried residue and filled up to the final volume with the aqueous vehicle (0.5% sodium carboxymethyl cellulose (CMC) in water). Due to the possibility to facilitate the structure elucidation of formed metabolites, 13C-test-substance will be added to the test substance preparation with 14C-test-substance for the balance experiments and for the bile excretion experiments. For these experiments, 13C-labeled test substance is mixed with non-labeled test substance in a ratio of 1 : 2 (w : w). In order to achieve the required specific activity, respective amounts of 14C-labeled test substance will be added. Each mixture will be filled up with the carrier to the final volume.

- Final dilution of a dissolved solid, stock liquid or gel: The test substance will be prepared in 0.5 % sodium carbodymethyl cellulose in tap water (CMC). 10 mL/kg bw of test substance preparation will be dosed orally by gavage.
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Crl:WI (Han)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, 97633 Sulzfeld, Germany
- Age at study initiation: 8-14 weeks
- Weight at study initiation: about 190 - 360 g prior to dosing
- Housing: During acclimatization and prior to the experiment animals will be housed in groups in polysulfonate cages. During the operation procedure for the bile experiments and multiple dosing of unlabeled test substance for balance experiments, animals are kept individually in Type III polycarbonate cages. During plasmakinetic and tissue distribution experiment animals will be kept individually in polycarbonate cages with steel wire mesh ground; from radio-labeled dosing on animals for the balance experiments will be kept in plastic metabolism cages, except for the two male animals where the exhaled air will be checked and animals in the bile excretion experiments which will be kept individually in all-glass metabolism cages type Metabowl.
- Diet (e.g. ad libitum): Kliba lab diet (mouse ( rat "GLP") either pelleted or meal (depending on the experimental conditions e.g. meal for balance experiments and pellets for plasmakinetics), ad libitum prior to and during the experiment
- Water (e.g. ad libitum): tap water ad libitum
- Acclimatization at least 5 days before treatment

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24 °C
- Humidity (%): 45 - 65 %
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 h / 12 h

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5 % in tap water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- Dose 1: 30 mg test substance / mL 0.5% sodium carboxymethyl cellulose in drinking water (tap water)
- Dose 2: 3 mg test substance / mL 0.5% sodium carboxymethyl cellulose in drinking water (tap water)

10 mL/kg body weight of a preparation will be administered to rats by gavage.
Duration and frequency of treatment / exposure:
Blood/plasma concentration:
- Experiment 1: 1 oral "high dose" with 300 mg/kg bw
- Experiment 2: 1 oral "low dose" with 30 mg/kg bw

Balance/excretion:
- Experiment 3: 1 oral "high dose" with 300 mg/kg bw
- Experiment 4: 1 oral "low dose" with 30 mg/kg bw
- Experiment 5: orally non-labeled once per day for 14 days, radio-labeled once on day 15 "low dose" 30 mg/kg bw

Excretion via bile:
- Experiment 6: 1 oral "high dose" with 300 mg/kg bw
- Experiment 7: 1 oral "low dose" with 30 mg/kg bw

Tissue distribution:
- Experiment 8: 1 oral "high dose" with 300 mg/kg bw
- Experiment 9: 1 oral "low dose" with 30 mg/kg bw
Doses / concentrationsopen allclose all
Dose / conc.:
30 mg/kg bw (total dose)
Remarks:
low dose
Dose / conc.:
300 mg/kg bw (total dose)
Remarks:
high dose
No. of animals per sex per dose:
- Experiments 1, 2, 3, 4 and 5: 4/sex/dose
- Experiments 6 and 7: 6/sex/dose
- Experiments 8 and 9: 12/sex/dose
Control animals:
no
Details on study design:
- Rationale for animal assignment (if not random): Type and duration of such studies require that animals of similar age are ordered sequentially in batches prior to the experiments. Therefore the conventional randomization and assignment to groups is not possible. Animals will be selected based on health status and to provide a narrow range of body weights (+/- 20 %).
- The administration route and doses were selected in relation to already performed studies
Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, blood, plasma, bile, cage wash
tissues checked for radioactivity:
heart, liver, spleen, bone, skin, lung, ovaries, carcass, muscle, kidney, testes, brain, pancreas, uterus, adipose tissue, stomach, stomach contents, thyroid gland, adrenal glands, blood cells, plasma, gut, gut contents, bone marrow

- Time and frequency of sampling: 1, 2, 4, 8, 24, 48, 72, 96, 120, 144, 268 hours (all dose groups)

ANALYTICAL METHODS
- LSC, Radio-HPLC, HPLC-UV
Statistics:
All relevant data are presented in appropriate summary tables. Group mean values and standard deviations were calculated. Radioactivity concentrations will be expressed in % of total dose administered. Analysis of kinetic data were performed based on the group mean values using the PC program system WinNonLin Version 8.0.
Parts of balance and tissue distribution experiments are presented in µg Eq/g in addition to % of total dose administered. The results of plasmakinetic experiments are presented in µg Eq/g only and not as % of total dose administered.

Results and discussion

Main ADME results
Type:
other: Kinetics

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The toxicokinetic parameters are summarized in Table 1.

HIGH DOSE (300 mg/kg bw) (experiment 1):
After administration of single oral dose of 300 mg/kg bw 14C-4,4'-sulphonyldiphenol, mean actual nominal doses of 305.5 and 304.7 mg/kg bw were achieved for males and females, respectively.
The maximum plasma concentrations (Cmax) of 58.16 and 27.48 μg Eq/g in males occurred 1 and 4 hours (Tmax) post dosing, respectively. The concentrations declined to 21.66 μg Eq/g at 24 hours post dosing and 0.85
μg Eq/g 72 hours post dosing and were below loq for all animals after 96 hours and the subsequent time points.
In female rats the maximum plasma concentrations (Cmax) of 104.93 and 26.47 μg Eq/g were reached 1 and 4 hours post dosing (Tmax). Within 72 hours post dosing, the plasma concentrations declined to 1.98 μg Eq/g at 72 hours and was below loq for all animals from 96 hours on and subsequent time points. Terminal half-lives were 10.3 and 14.7 hours, for males and females, respectively .
The area under the plasma concentration time curve (AUC0-->∞) was 1005 μg Eq*h/g and 1083 μg Eq*h/g for males and females respectively, based on group mean values

LOW DOSE (30 mg/kg bw) (experiment 2):
Mean actual nominal doses of 30.2 and 30.3 mg/kg bw were achieved for males and females, respectively, in rats after oral exposure to a single dose of 30 mg/kg bw 14C-4,4'-sulphonyldiphenol. In male rats the Cmax were measured 1 and 4 hours post dosing with 8.66 and 3.81 μg Eq/g, respectively. Declining to 0.13 μg Eq/g at 48 hours post dosing and were below loq for all animals at 72 hours post dosing and the subsequent time points. In female rats, Cmax of 6.59 and 4.55 μg Eq/g were reached 1 and 4 hours post dosing.
After that, the concentration declined to 0.01 μg Eq/g at 72 hours post dosing (concentrations below loq for 3 of 4 animals) and further decreased for all animals. After 96 hours and subsequent time points no quantitation was possible. Terminal half-lives were
9.2 and 8.9 hours, for males and females, respectively.
The AUC0-->∞ was calculated to be 74 μg Eq*h/g and 80 μg Eq*h/g for males and females respectively (calculations based on group mean values).

The plasmakinetic data of 14C-4,4'-sulphonyldiphenol show fast absorption of the test substance after oral administration from the gastrointestinal tract, leading to a dose dependent increase in maximum plasma concentrations with first Tmax-values of generally 1 h post dosing. The observation of a second Cmax-value at later TMax (at 4 hours post dosing) for both dose levels and genders indicate a potential enterohepatic recirculation of the test substance and/or its metabolites. At higher doses, these data indicate a potential saturation of kinetics, which may be caused by potential active transport of the test substance and/or its metabolites.

Oral absorption was calculated to be about 93 and 96% of the administered dose at a dose level of 300 mg/kg bw for male and female rats, respectively. At the low dose level (30 mg/kg bw) 95% (males) and 87% (females) of the administered dose were absorbed.
Details on distribution in tissues:
Following a single oral dose of 14C-4,4'-sulphonyldiphenol at a dose level of 300 mg/kg bw, tissue distribution was measured 1, 4, 36 and 46 hours post-dosing in males and 1, 4, 37 and 50 hours post-dosing in females. At the low dose level of 30 mg/kg bw, the corresponding radioactivity measurements were performed 1, 4, 18 and 25 hours as well as 1, 4, 17 and 22 hours after administration in males and females, respectively.

HIGH DOSE (300 mg/kg bw 14C-4,4'-sulphonyldiphenol),1 hour after administration:
In both sexes the highest tissue concentrations (means) were found in the GI-tract/GI-tract contents.
In male rats with exception of the GI-tract (including its content), highest residues (means) were found in kidney (100.61 μg Eq/g), liver (67.88μg Eq/g), plasma (57.39μg Eq/g), carcass 49.42μg Eq/g), lung (33.22μg Eq/g) and skin (30.64 μg Eq/g) and lowest mean radioactive residues at this time point were measured in adipose tissue, brain and bone with concentrations of 3.49, 4.30 and 4.81 μg Eq/g.
In female rats with the exception of the GI-tract (including its content), highest residues (means) in female rats 1-hour post dosing were found in brain, plasma liver, thyroid, pancreas, lung, skin and carcass with concentrations of 78.51, 65.22, 64.40, 44.63, 43.33, 40.89, 40.83 and 39.87 μg Eq/g, respectively. Lowest mean radioactive residues at this time point were measured in adipose tissue (5.46 µg Eq/g), bone (5.74 µg Eq/g) and kidney (6.61 μg Eq/g).

LOW DOSE (30 mg/kg bw 14C-4,4'-sulphonyldiphenol), 1 hour after oral administration:
In both sexes the highest tissue concentrations (means) were found in the GI tract/GI-tract contents. With the exception of the GI-tract (including its content), highest residues (means) in male rats were found in liver and kidney, resulting in 19.25 and 16.17 μg Eq/g. For male animals, lowest mean radioactive residues at this time point were measured in brain, adipose tissue and bone with values ranging between 0.42 and 0.79 μg Eq/g.
With the exception of the GI-tract (including its content), highest residues (means) in female rats 1 hour post oral dosing of 30 mg/kg bw 14C-4,4'-sulphonyldiphenol were found in liver, kidney and thyroid with concentrations of 8.76, 7.12 and 5.39 μg Eq/g. For female animals, lowest mean radioactive residues at this observation time point were measured in brain, bone, adipose tissue and muscle (values between 0.18 and 0.57 µg Eq/g).
For both sexes and in both dose groups, radioactive residue concentrations generally declined in organs and tissues from the 1 h time point on and paralell to the radioactive residues in plasma. In contrast to this general trend, radioactive residues in carcass decreased slower than in other organs and tissues, especially in the high dose group tested.
With the exception of radioactive residues in carcass samples, tissue distribution experiments showed a generally sublinear correlation between the radioactive residues in organs and tissues and the administered dose. For carcass samples, the radioactive residues are overproportional to dose. This overproportional ratio is more pronounced at later sampling time points.
Details on excretion:
BALANCE/EXCRETION:
HIGH DOSE (300 mg/kg bw) (experiment 3):
Mean total recoveries of radioactivity:Male rats 95.14% and 98.58 % in female rats, respectively.
The urinary excretion occurred predominantly within 48 hours after exposure. Within 48 hours after single oral administration of 300 mg/kg bw to male and female rats 41.30 and 34.00 % of the administered radioactivity were found in urine, respectively. After 168 hours the total urinary excretion of radioactivity was 48.05 and 39.02 % of dose for males and females, respectively.
38.74 % (males) and 50.13 % (females) of the administered radioactivity were excreted within the first 48 hours via feces. After 168 hours the total amount of radioactivity excreted via feces was found to be 44.20 and 55.71 % of dose
for males and females, repectively.
Major excretion of absorbed 14C-4,4'-sulphonyldiphenol occurs within 48 hours after dosing. Together with cage wash, the total amount of excreted radioactivity was found to be 94.81 % of the administered radioactivity in males and 97.33 % of the administered radioactivity in females reflecting more or less complete excretion of orally dosed 14C-4,4'-sulphonyldiphenol for male and femalte rats. 168 hours post-dosing, small amounts with contents ranging from 0.01-1.16% of the dose of 14C-4,4'-sulphonyldiphenol were found in skin, carcass, gut and stomach contentand gut content for male and female animals.

LOW DOSE (30 mg/kg bw) (experiment 4):
Mean total recoveries of radioactivity: 105.33% (males) and 97.17 % (females). Negligible amounts (< 0.1% of the administered dose) were measured in exhaled air.
Excretion in urine within 48 hours after single oral administration contributed to 56.94% in male rats and 47.09% in female rats of the administered radioactivity. Total excretion of radioactivity via urine after 168 hours was 60.13 and 51.45 % of dose for males and females, respectively.
Urinary excretion predominantly takes place within 48 hours after test substance adminstration.
During the first 48 hours after administration, 41.75 % and 39.40 % of the administered radioactivity were excreted via feces by males and females, respectively. After 168 hours the total amount of radioactivity excreted via feces was found to be 43.00 and 40.85 % of dose
for males and females, repectively.
Also, fecal excretion occurs mainly within the first 2 days after administration of the substance.
Together with cage wash, the total amount of excreted radioactivity was found to be 104.33% of the administered radioactivity in males and 96.06 % of the administered radioactivity in females reflecting more or less complete excretion of orally dosed 14C-4,4'-sulphonyldiphenol
for male and female rats. 168 hours post-dosing, only traces of radioactive residues of 14C-4,4'-sulphonyldiphenol were found in carcass, skin, stomach content, gut content and gut. Highest total radioactive residues (in μg Eq/g) 168 h post dosing (except GI tract)
were found in carcass for both sexes, for all other tissues the residues ranged between 0.0
and 0.1 μg Eq/g.

EXPERIMENT 5 (14 days once daily non-labeled, radio-labeled once on day 15, 30 mg/kg bw):
Mean total recoveries of radioactivity were 96.21 and 99.69% of dose in male and female rats, respectively.
Predominantly excreted within 48 hours after administration via urine and feces. The balance data demonstrate that excretion of 14C-4,4'-sulphonyldiphenol dosed orally by gavage to Wistar rats at a single low and high dose as well as multiple low dose (14 + 1) was fast via urine and feces. Urinary excretion was slightly higher than fecal excretion for male animals of both dose groups and female animals of the low dose group, single and multiple dosing, whereas for female animals of the high dose group, excretion via urine was about 17 % lower than fecal excretion. Excretion was almost complete and occurred to a major extent within two days after oral dosing.
The excretion of 14C-4,4'-sulphonyldiphenol in the low dose is independent from frequency of treatment and gender.

EXCRETION VIA BILE
HIGH DOSE (300 mg/kg bw):
Mean total recoveries of radioactivity were 93.83 and 97.55% of dose in male and female rats, respectively.
Within 72 hours after administration: excretion via bile 43.81% (males) and 45.65% (females)

The bile excretion experiments show that excretion of 14C-4,4'-sulphonyldiphenol dosed orally by gavage to Wistar rats with single doses of 300 and 30 mg/kg bw was fast and occurred mainly via urine (HIGH DOSE: 47.52 (males) and 48.91% (females); LOW DOSE: 37.72 (males) and 46.37 % (females)) and via bile (HIGH DOSE: 43.81 (males) and 45.65 % (females); LOW DOSE: 56.39 (males) and 38.21 % (females) for both dose levels.
Compared to the balance experiments, mean urinary excretions were generally lower in bile excretion experiments, except for females of the high dose experiment, demonstrating reabsorption of the test substance into the systemic circulation under physiological conditions. This finding correlates to indications for potential enterohepatic recirculation obtained in plasmakinetic experiments.
Toxicokinetic parameters
Toxicokinetic parameters:
other: Parameters in Table 1
Remarks:
Toxicokinetic parameters are displayed in Table 1

Any other information on results incl. tables

Table 1: Plasma toxicokinetic parameters

 Sex

 dose [mg/kg bw]

 Cmax [µg Eq/g]

 Tmax [h]

 half life [h]

 AUC [µg Eq*h/g]ex

 male 300   58.16; 27.48  1; 4  10.3  1005
 male  30  8.66; 3.81  1; 4  9.2  74
 female  300  104.93; 26.47  1; 4  14.7  1083 
 female  30  6.59; 4.55  1; 4  8.9  80

Applicant's summary and conclusion

Executive summary:

14C-4,4'-sulphonyldiphenol showed fast absorption from the gastrointestinal tract. Based on the bile excretion experiments, oral absorption was calculated to be about 93 and 96 % of the administered dose at a dose level of 300 mg/kg bw for male and female rats, respectively. At a dose level of 30 mg/kg bw about 95% of the administered dose was absorbed for males and 87% of the administered dose were absorbed by females. The excretion of radioactivity occurred mainly within two days after dosing, mainly via urine and bile in bile excretion experiments and with a generally, slightly higher excretion in urine than in feces in balance experiments. Plasma kinetics confirmed high oral absorption and demonstrated potential enterohepatic recirculation, fast excretion and a slight supralinear correlation of the internal exposure to the oral dose. In tissue distribution experiments, residues of 14C-4,4'-sulphonyldiphenol and/or its metabolites in organs and tissues showed generally sublinear correlation between radioactive residues in organs and tissues and administered oral doses. However, supralinear correlation between radioactive residues in carcass and the external dose was observed in these experiments that is in relation to the findings of plasmakinetics.