4,4'-sulphonyldiphenol

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

dermal absorption

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Simulation of dermal absorption based on LogP

Justification for type of information:

QSAR prediction

Qualifier:

according to guideline

Guideline:

other: OECD Series on Testing and Assessment No. 69 (Validation of QSAR)

Qualifier:

according to guideline

Guideline:

other: US EPA, 1992. Dermal Exposure Assessment: Principles and Applications. EPA/600/8-91-011B, Interim Report.

Principles of method if other than guideline:

The dermal permeability coefficient program (DERMWIN v2.00) estimates the dermal permeability coefficient (Kp), the dermally absorbed dose per event (DAevent) and dermal absorbed dose (DAD) for a dilute organic chemical in an aqueous solution.

GLP compliance:

no

Kp (est): 0.000387 cm/hr

CAS No.: 000080-09-1

SMILES : O=S(=O)(c(ccc(O)c1)c1)c(ccc(O)c2)c2

CHEM : Phenol, 4,4 -sulfonylbis-

MOL FOR: C12 H10 O4 S1

MOL WT : 250.27

------------------------------ Dermwin v2.00 ----------------------------------

Log Kow (estimated) : 1.65

Log Kow (user-entered): 1.20 (used in Kp calculations)

GENERAL Equation: log Kp = -2.80 + 0.66 log Kow - 0.0056 MW

Kp (predicted): 3.87e-004 cm/hr

Dermally Absorbed Dose per Event for Organic Compounds - Water Contact: Water Conc (mg/cm3): 1.1 (entered by user)

Fraction Absorbed : 1.0000

DA(event): 5.71e-003 mg/cm2-event (using eqn 3.2 & 3.3)

(tau = 2.7 hr, t* = 6.48 hr)

Dermally Absorbed Dose (70 kg Adult) - Water Contact: DAD: 6.03e-001 mg/kg-day (using eqn 3.1)

Reference 2

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Mar 2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 428 (Skin Absorption: In Vitro Method)

Version / remarks:

2004

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

The Department of Health of the Government of the United Kingdom

Specific details on test material used for the study:

RADIOLABELLED TEST ITEM

SOURCE OF TEST MATERIAL
- Lot No. of test material: 372-058-0601-A-20150313-DRE

RADIOLABELLING INFORMATION (if applicable)
- Radiochemical purity: 99.7%
- Specific activity: 238.3 µCi/mg 60.1 mCi/mmol
- Locations of the label: [14C(U)]-

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: -20 °C
- Stability under test conditions: The results of the radiochemical purity assessment confirmed that the test item was stable over the dosing period.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Ethanol (10 mL) was added to the radiolabelled test substance vieal. The contents were mixed by vortex. Three aliquots (10 µL) of the stock stolution were transferred into scintillation vials, mixed with methanol:scintillation fluid and analysed by liquid scintillation counting. The concentration of test item in the stock solution was determined to be 0.527 +/- 0.0141 mg/mL with a CV of 2.66 %.
- Final preparation of a solid:
Preparation at lower specific activity: The test item was added to a 2 mL volumetric flask. Stock solution was added to the flask. Ethanol was added up to the 2 mL calibration line and the sample was mixed by vortex for ca. 1 min. Three aliquots (10 µL) were taken, mixed with methanol:scintillation fluid and analysed by liquid scintillation counting. By radioactivity, the concentration of the radiolabelled test item in the solution was determined to be 2.31 mg/mL. The test item was homogeneously distributed in the solution with a CV of 0.91 %. The new specific activity determined was 13.7 µCi/mg.
Test Preparations: The test substance was added to a glass vial in aliquots. The solvent was removed under a gentle stream of nitrogen gas after the addition of each aliquot. Physiological saline was added to the vial in small aliquots and the contents were mixed by vortex. Six aliquots were taken, mixed with methanol:scintillation fluid and analysed by liquid scintillation counting.
- Batch No.of test material: 161106
- Expiration date of the lot/batch: 16 November 2019
- Purity: 99.51%
- Physical appearance: white powder

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: ambient
- Solubility and stability of the test substance in the solvent/vehicle: The test substance was predicted to have a water solubility of 1.1 g/L (Sponsor's supplied information). For an application of 500 µL/cm² over a 0.64 cm² application area, for the highest concentration formulation (200 mg/L, Test Preparation 3), 320 µL of the formulation (0.064 mg of BPS) would be applied to each skin sample. Theoretically, if 100 % of the test item was absorbed, this would result in a test item concentration in the receptor fluid of 12.8 mg/L (0.064 mg of BPS in 5 mL of receptor fluid). The solubility of BPS in the receptor fluid was assessed assuming 10 x 100 % absorption; therefore, the target concentration of BPS in the receptor fluid for the solubility assessment was 0.128 g/L.

Radiolabelling:

yes

Species:

other: ex vivo study

Strain:

other: human skin stratum corneum samples

Sex:

female

Type of coverage:

open

Vehicle:

physiological saline

Duration of exposure:

8 h exposure period with an additional 16 h monitoring period

Doses:

1 and 102 µg/cm2

No. of animals per group:

8 split-thickness samples of human skin

Control animals:

no

Details on study design:

DOSE PREPARATION
- Method for preparation of dose suspensions: The test substance was added to a glass vial in aliquots. The solvent was removed under a gentle stream of nitrogen gas after the addition of each aliquot. Physiological saline was added to the vial in small aliquots and the contents were mixed by vortex. Six aliquots were taken, mixed with methanol:scintillation fluid and analysed by liquid scintillation counting.

APPLICATION OF DOSE: The test substance preparations were applied to the surface of the exposed stratum corneum of 8 split-thickness samples of human skin, respectively, using a positive displacement pipette set. The donor chambers of the cells were not occluded and so were left open to the atmosphere. Seven representative aliquots in the test preparations were dispensed into vials at the time of dosing, mixed with methanol:scinitillation fluid and analysed by liquid scintillation counting.

REMOVAL OF TEST SUBSTANCE
- Washing procedures and type of cleansing agent: The applied dose was removed from the exposed skin surface from samples dosed with 200 mg/L test preparation only. Commercial hand wash soap (ca. 50 µL) was applied to the skin and the soap gently rubbed onto the skin with a tissue swab. The skin was then rinsed with ca. 5 mL of a ca. 2% (v/v) commercial soap solution. The soap solution was applied in aliquots (0.5 mL) and each aliquot was aspirated three times with a pipette. The skin was dried with a tissue swab. The process was repeated and the skin was dried with an additional tissue swab.
- Time after start of exposure: 8 h

SAMPLE PREPARATION
- Storage procedure: in a freezer set to maintain a temperature of -20 °C
- Preparation details: Four samples of full-thickness human skin (three samples from the abdominal site and one single sample obtained from abdomen and back region) were obtained from female donors aged 39 to 72 years old. Two of the skin samples were obtained NHS Lothian on ice. On arrival, the subcutaneous fat and connective tissue were removed from the skin samples using a scalpel. The samples were washed under cold running tap water and dried with paper towels. The samples were cut into pieces, vacuum packed and stored at - 20 °C until they were used for the study. Two of the samples were obtained from Tissue Solutions, Glasgow. The samples arrived deep frozen on dry ice and were stored in a freezer set to maintain a temperature of -20 °C until they were used for the study. The age and sex of the donor and sites from which the skin samples were taken were recorded in the study records. Human skin samples were removed from - 20 °C storage and allowed to thaw at ambient temperature. The thickness of the full-thickness skin membranes was measured using a micrometer. Split-thickness membranes were prepared by pinning the full-thickness skin, stratum corneum uppermost, onto a raised cork board and cutting with an electric dermatome at a setting equivalent to 200 - 400 µm depth. The thickness of the split-thickness membranes was measured using a micrometer. Membranes were then wrapped in aluminium foil and stored in a freezer, set to maintain a temperature of -20 °C, for a maximum period of two months.

ANALYSIS
- Method type(s) for identification: Liquid scintillation, HPLC-UV
- Validation of analytical procedure: All samples were counted together with the representative blanks using a liquid scintillation analyser with automatic quench correction by external standard. Scintillation fluid (10 mL) or methanol:scintillation fluid (12 mL) was added to the samples. Representative blank sample values were substracted from sample count rates to give net dpm per sample. Prior to analysis, samples were allowed to stabilise with regard to light and temperature.
- Limits of detection and quantification: A limit of reliable measurement of 30 dpm above background has been instituted in these laboratories. Counts that are below 30 dpm above background represent a true value. This means that data are recorded with values that are less than the limit of reliable measurement.

Details on in vitro test system (if applicable):

SKIN PREPARATION
- Source of skin: full-thickness human skin
- Ethical approval if human skin: female donors aged 39 to 72 years old
- Type of skin: three samples from the abdominal site and one single sample obtained from abdomen and back region
- Preparative technique: The thickness of the full-thickness skin membranes was measured using a micrometer. Split-thickness membranes were prepared by pinning the full-thickness skin, stratum corneum uppermost, onto a raised cork board and cutting with an electric dermatome at a setting equivalent to 200 - 400 µm depth. The thickness of the split-thickness membranes was measured using a micrometer.
- Thickness of skin (in mm): Full Thickness Skin: 1340 µm, 1420 - 2000 µm, 1200 µm, 1690 µm; Split-Thickness Skin: 400 µm, 390 - 400 µm, 400 µm, 400 µm
- Membrane integrity check: Skin samples were allowed to equilibrate at 32 °C +/- 1 °C for ca. 5 min. Phosphate buffered saline (1 mL) was then added to the donor chamber and the skin samples were allowed to equilibrate for a further ca. 30 min. The electrical resistance was then measured using a Tinsley Databridge (Model 6401) set at low voltage alternating current, 1000 Hz with a maximum voltage of 300 mV root-mean-squared (rms) in the parallel equivalent circuit mode. Any skin sample exhibiting a resistance less than 10.9 kΩ (threshold value) was excluded from subsequent absorption measurements. The phosphate buffered saline was removed from the skin surface, which was then rinsed with water and dried with tissue paper.
- Storage conditions: -20 °C

PRINCIPLES OF ASSAY
- Diffusion cell: The glass static diffusion cells were placed in a manifold on a magnetic stirrer plate heated via a circulating water bath to maintain the skin surface temperature at 32 °C +/- 1 °C. The surface area of exposed skin within the cells was 0.64 cm². The receptor chamber volume was nominally 5 mL, with each receptor chamber individually marked with the actual volume by the manufacturer.
- Receptor fluid: Phosphate buffered saline containing polyoxyethylene 20 oleyl ether (PEG, ca. 6%, w/v), sodium azide (ca. 0.01%, w/v), streptomycin (ca. 0.1 mg/mL) and penicillin (ca. 100 units/mL). The pH of the receptor fluid was confirmed to be 7.36.
- Solubility of test substance in receptor fluid: The test substance was predicted to have a water solubility of 1.1 g/L (Sponsor's supplied information). For an application of 500 µL/cm² over a 0.64 cm² application area, for the highest concentration formulation (200 mg/L), 320 µL of the formulation (0.064 mg of BPS) would be applied to each skin sample. Theoretically, if 100 % of the test substance was absorbed, this would result in a test item concentration in the receptor fluid of 12.8 mg/L (0.064 mg of BPS in 5 mL of receptor fluid). The solubility of the test substance BPS in the receptor fluid was assessed assuming 10 x 100 % absorption; therefore, the target concentration of BPS in the receptor fluid for solubility assessment was 0.128 g/L.
- Static system: The receptor chambers were in a manifold connected to a circulating waterbath. Magnetic stirrer bars were placed in the receptor fluid chambers which were filled with receptor fluid. Split-thickness skin samples were removed from the freezer and allowed to thaw at ambient temperature. Sections of split-thickness skin (ca. 1.5 x 1.5 cm) were cut and mounted in the diffusion cells between the donor and receptor chamber. The donor chamber was tightened into place with a clamp. Cells were visually checked to ensure no cells were leaking and no air bubbles were present in the receptor fluid chamber.
- Test temperature: ambient
- Occlusion: open

Absorption in different matrices:

- Absorption:
102 µg/cm2: The mean absorption rate through human split-thickness skin was 2.64 ng equiv./cm²/h during the 24 h experimental period
1 µg/cm2: The mean absorption rate through human split-thickness skin was 0.06 ng equiv./cm²/h during the 24 h experimental period
- Penetration:
102 µg/cm2: The amount penetrated at 24 h as measured in the receptor fluid was 63.4 ng equiv./cm², which is equivalent to 0.06 % of the applied dose
1 µg/cm2: The amount penetrated at 24 h as measured in the receptor fluid was 1.43 ng equiv./cm², which is equivalent to 0.14 % of the applied dose
- Stratum corneum (in vitro test system): tape strips

Time point:

24 h

Dose:

102 µg/cm2

Parameter:

rate

Absorption:

2.64 other: ng equiv./cm2/h

Time point:

24 h

Dose:

102 µg/cm2

Parameter:

percentage

Absorption:

1.8 %

Time point:

24 h

Dose:

1 µg/cm2

Parameter:

rate

Absorption:

0.06 other: ng equiv./cm²/h

Time point:

24 h

Dose:

1 µg/cm2

Parameter:

percentage

Absorption:

8.79 %

Table 1: Cumulative absorption of all donors, 102 µg/cm2 test item

Time [h]	Mean cumulative penetration [µg equiv./cm²]
0 1 2 4 8 12 24	0.00000 0.00007 0.00186 0.00476 0.01067 0.02242 0.06336

Table 2: Cumulative absorption of all donors, 1 µg/cm2 test item

Time [h]	Mean cumulative penetration [µg equiv./cm²]
0 1 2 4 8 12 24	0.00 0.00 0.04 0.22 0.35 0.88 1.43

Following topical (infinite dose) application of 200 mg/L test preparation to human skin in vitro, the absorbed dose was 0.08 +/- 0.08 % (0.08 +/- 0.08 µg equiv./cm²) of the applied dose. The dermal delivery was 0.56 +/- 0.19 % (0.57 +/- 0.20 µg equiv./cm²) of the applied dose. The potentially absorbed dose was 1.80 +/- 0.38 % (1.84 +/- 0.39 µg eqiv./cm²) of the applied dose. The mass balance was 100.26 +/- 0.26 % (102 +/- 0.26 µg equiv./cm²) of the applied dose.

Following topical (finite dose) application of 100 mg/L to human skin in vitro, the absorbed dose was 0.19 +/- 0.21 % (1.94 +/- 2.15 ng equiv./cm²) of the applied dose. The dermal delivery was 1.66 +/- 1.00 % (17.2 +/- 10.3 ng equiv./cm²) of the applied dose. The potentially absorbed dose was 8.79 +/- 3.24 % (90.8 +/- 33.4 ng equiv./cm²) of the applied dose. The mass balance was 100.40 +/- 0.96 % (1037 +/- 9.87 ng equiv./cm²) of the applied dose.

Executive summary:

The test item is used in a variety of products commercially.

The aim of this study was to determine the rate and extent of absorption of the test substance following topical application to human skin.

Split-thickness human skin membranes were mounted into static diffusion cells in vitro. Receptor fluid was added to the receptor chamber (nominal volume 5 mL, nominal exposure are 0.64 cm²). The skin surface temperature was maintained at 32 °C +/- 1 °C throughout the experiment. An electrical resistance barrier integrity assessment was performed and any skin sample exhibiting resistance lower than 10.9 kΩ was excluded from subsequent absorption measurements.

The test preparations were applied (500 µL/cm² or 10 µL/cm²) to human split-thickness skin membranes obtained from four different donors and the cells were left open to the atmosphere. The concentration of the test substance in the test preparations was 200 mg/L for infinite dose and 100 mg/L for finite dose applications. The application rate of the test item was 102 µg/cm2 and 1 µg/cm2. The stability throughout the application of all test preparations was confirmed by high performance liquid chromatography (HPLC).

Percutaneous absorption was assessed by collecting receptor fluid samples prior to dosing and at 1, 2, 4, 8, 12 and 24 h post dose. At 8 h post dose, the exposure period was terminated by removing the applied test preparation from the skin surface (where applicable) and washing the skin surface with a concentrated commercial hand wash soap followed by rinsing with a dilute soap solution (2 %, v/v) and drying the surface with a tissue swab. At 24 h post dose, the skin was removed from the static cells, the stratum corneum tape stripped and the skin divided into epidermis, dermis and unexposed skin samples. The skin samples were dissolved with Solvable tissue solubiliser. All samples were analysed by liquid scintillation counting.

Following topical (infinite dose) application of 200 mg/L test preparation to human skin in vitro, the absorbed dose was 0.08 +/- 0.08 % (0.08 +/- 0.08 µg equiv./cm²) of the applied dose. The dermal delivery was 0.56 +/- 0.19 % (0.57 +/- 0.20 µg equiv./cm²) of the applied dose. The potentially absorbed dose was 1.80 +/- 0.38 % (1.84 +/- 0.39 µg eqiv./cm²) of the applied dose. The mass balance was 100.26 +/- 0.26 % (102 +/- 0.26 µg equiv./cm²) of the applied dose.

Following topical (finite dose) application of 100 mg/L to human skin in vitro, the absorbed dose was 0.19 +/- 0.21 % (1.94 +/- 2.15 ng equiv./cm²) of the applied dose. The dermal delivery was 1.66 +/- 1.00 % (17.2 +/- 10.3 ng equiv./cm²) of the applied dose. The potentially absorbed dose was 8.79 +/- 3.24 % (90.8 +/- 33.4 ng equiv./cm²) of the applied dose. The mass balance was 100.40 +/- 0.96 % (1037 +/- 9.87 ng equiv./cm²) of the applied dose.

Reference 3

Endpoint:

dermal absorption in vivo

Remarks:

Human clinical study

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

GLP compliance:

not specified

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source: Toronto Research Chemicals

- 4,4'-sulfonylbisphenol-d8: purity: >99%, isotopic purity > 98%
- Locations of the label: d8

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing:
BPS was suspended in a 0.1 M phosphate buffer (pH 7.4) containing 1% sodium carboxymethylcellulose of medium viscosity (100 µg/µL) and applied as drops (700 µL for an individual of 70 kg).

Species:

other: Human

Sex:

female

Type of coverage:

open

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

0.1 M phosphate buffer (pH 7.4) containing 1% sodium carboxymethylcellulose

Duration of exposure:

6 h

Doses:

1 mg/kg bw

No. of animals per group:

6 female volunteers

Control animals:

no

Details on study design:

DOSE PREPARATION
- Method for preparation of dose suspensions: BPS was suspended in a 0.1 M phosphate buffer (pH 7.4) containing 1% sodium carboxymethylcellulose of medium viscosity (100 mg/mL or 100 μg/μL) (a synthetic gel used against dry eye and as a food additive) and applied as drops (700 μL for an individual of 70 kg).

APPLICATION OF DOSE:
About 48 h before dermal application of BPS, participants were recommended to remove hair on their forearm while taking care not to irritate the skin. The solution was then applied to an area of 40 cm2 of the forearm.

VEHICLE
- Amount(s) applied (volume or weight with unit): 1 mg/kg bw; (BPS suspended in 0.1 M phosphate buffer (pH 7.4) containing 1% sodium carboxymethylcellulose of medium viscosity)
- Concentration (if solution): 100 mg/mL

TEST SITE
- Preparation of test site: 48 h before dermal application, hair was removed at the application site
- Area of exposure: 40 cm²
- % coverage: no coverage
- Time intervals for shavings or clipplings: 48 h before application

REMOVAL OF TEST SUBSTANCE
- Washing procedures and type of cleansing agent: wiped and washed with soap and water
- Time after start of exposure: 6 h

SAMPLE COLLECTION
- Collection of blood: 30 min before exposure; 15 min, 30 min, 45 min, 1 h, 1 h 15, 1 h 30,
1 h 45, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 24 h and 48 h post-dosing
- Collection of urine: nocturnal collection before exposure (-10 h-0 h) and
0–2 h, 2–4 h, 4–6 h, 6–8 h, 8–10 h, 10–12 h, 12–14 h, 14–24 h, 24–48 h
and 48–72 h post-administration

SAMPLE PREPARATION
- Storage procedure: Immediately after collection, blood samples were stored at 4 °C. Urine samples were stored in the refrigerator at 4 °C immediately after collection the first day of sampling or kept in coolers with ice packs afterwards by participants until arrival at the lab.

- Preparation details: Within the hour following blood withdrawal, plasma was isolated by centrifuging samples for 10 min at 1500 g at 4 °C. Four aliquots of 1 mL were prepared in polypropylene tubes with Fischer screw cap of 2 mL and then samples frozen at −20 °C. Two aliquots were shipped one dry ice at INRA in Toulouse for analysis of BPS-d8 and BPSG-d8.
Urine volumes were measured the day of collection. For each sample, 3 aliquots of 3 mL were prepared in 5 mL polypropylene tubes and 1 aliquot was prepared of 90–100 mL in a 120 mL Sarstedt container. Samples were subsequently frozen at −20 °C until analysis. Aliquots were shipped on dry ice for analysis at INRA in Toulouse.

ANALYSIS
- Method type(s) for identification: online SPE; UPLC-MS-MS
- Validation of analytical procedure: according to European Medicine Agency Guidelines from 0.05 to 10 ng/mL (i.e. 0.2 to 39 nM) for BPS-d8 using a linear model weighted by 1/X (X=concentration) and from 0.5 to 100 ng/mL (i.e. 1.15 to 230 nM) for BPSG-d8 using a linear model weighted by 1/X².
Coefficient of variation (CV%): levels (0.08, 0.8 and 8 ng/mL): CV% < 17% for BPS-d8 and 9% for BPSG-d8 with accuracy ranging from 80% to 96% for both molecules.
- Limits of detection and quantification: LLOQ (plasma) at 0.05 and 0.5 ng/mL (i.e 0.2 and 1.15 nM) and in urine at 0.5 and 5 ng/mL (i.e. 2 and 11.5 nM) for BPS-d8 and BPSG-d8, respectively. The limits of detection (LOD) were estimated at 0.02 and 0.14 ng/mL (i.e. 0.08 nM
and 0.32 nM) in plasma for BPS-d8 and BPSG-d8, respectively.

Dermal irritation:

not specified

The individual time courses of BPS-d8 and BPSG-d8 in plasma over a 48-h period following the onset of a 6-h cutaneous application of 1 mg/kg bw of BPS-d8 in volunteers showed values below the lower limit of quantification (LLOQ) for most time points such that average time course were not reported. The low levels did not allow to determine toxicokinetic parameters. 

Nevertheless, an increase in plasma levels of both compounds was detectable from individual profiles. Peak values were reached between 5 and 8 hours after application. BPSG-d8 was found in higher molar concentrations than BPS-d8 (2- to 9-fold at peak levels).

Limited amounts of BPS-d8 and its conjugate were recovered in urine. Peak excretion was reached between 5 and 11 hours postdosing. BPSG-d8 is excreted slower than BPS-d8 over the 72h collection period, however levels were close to the LLOQ, thus the results have to be considered with caution. The cumulative excretion time courses of BPS-d8 and BPSG-d8 show that BPSG-d8 is excreted in about 20-times higher amounts than BPS-d8, and that excretion is not totally complete after 72 h (lack of asymptote)  for part of the volunteers.

The average percent (±SD) of the administered dose recovered in urine as BPS-d8 and BPSG-d8 was about 0.004 ± 0.003 and 0.09 ± 0.07%, respectively. This suggests a rather low relative bioavailability by the cutaneous route when compared to the oral route.

Executive summary:

6 female volunteers were dermally exposed on their forearms to 1 mg/kg bw BPS for 6 h. Dermal time course values were too close or below the limit of detection or quantification to provide a direct comparison with the oral kinetic data. As observed for the absorption after oral exposure, dermal absorption of BPS is fast and the elimination after dermal application of a low dose appears not to be complete after 72 h.

The average percent (±SD) of the administered dose recovered in urine as BPS-d8 and BPSG-d8 was about 0.004 ± 0.003 and 0.09 ± 0.07%, respectively. This suggests a very low relative bioavailability by the cutaneous route when compared to the oral route.

Reference 4

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

absorption

distribution

Qualifier:

no guideline followed

GLP compliance:

not specified

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source: Sigma Aldrich

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing:
powder was mixed with 2.5% CMC

FORM AS APPLIED IN THE TEST (if different from that of starting material)
- solution

Radiolabelling:

no

Species:

other: piglet

Strain:

other: Large White Breed

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: GIE Ville franche Grand Sud-Villefranche de Rouergue, Marquié-Saint Ybars, and Calvignac-St.Vincent d’Autejac)
- Age at study initiation: 28 to 42 days
- Weight at study initiation: 8.75 to 27.82 kg
- Housing: piglets were housed in a 12 m² force-ventilated room
- Diet: Piglets weighing less than 12 kg were fed a postweaning food (PrimeFeed;Vilofoss), the piglets over 12 kg were fed with a flour-based growth food (PS2;Solieval).
- Water: ad libitum
- Acclimation period: not specified

ENVIRONMENTAL CONDITIONS
- Temperature (°C): approx. 25
- Humidity (%): not specified
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12/12 h

Route of administration:

other: see "Datails on exposure"

Vehicle:

other: see "Datails on exposure"

Details on exposure:

IV administration:
Exp. 3, 4 and 5: BPS powder was dissolved in ethanol–saline (1:2, vol:vol) at 25 mg/ml (Exp. 3 and 4) and 50 mg/mL (Exp. 5)

administration by gavage
Exp. 4: BPS powder was placed in a Luer-lock syringe, mixed with 2.5% (w/v) carboxymethylcellulose in 0:1 M phosphate buffer containing sucrose (146mg/mL) using a syringe adaptor, to yield a carboxymethylcellulose gel containing 10mg/ml of BPS.
Exp. 5: For the cocktail approach, BPA and BPS were both dissolved in ethanol–corn oil (1:7, vol:vol) at 25 mg/mL

Duration and frequency of treatment / exposure:

Experiment 1 and 2 were performed using BPA.
Experiment 3 and 4 used BPS. Six female piglets age 28 days were adminstered BPS intravenously. Each piglet received two successive intravenous administrations of BPS and BPS-glucuronide at respective doses of 20 µmol/kg (5 mg/kg) and 2.23 µmol/kg (1 mg/kg), 72 h apart. The fourth experiment was performed in 6 female piglets age 28 d to specifically evaluate the extent of BPS absorption by oral route and to measure the systemic bioavailability of BPS. The experiment was divided into two periods separated by 72 h, during which the piglets were administered BPS respectively at the dose of 20 µmol/kg (5 mg/kg) by intravenous route and at a dose of 40 µmol/kg (10 mg/kg) by gavage.
Experiment 5 was performed to directly compare BPA and BPS disposition after IV and oral administration.

Dose / conc.:

5 mg/kg bw/day

Remarks:

20 µmol BPS/kg, IV (Exp. 3 and 4), gavage (Exp. 5)

Dose / conc.:

10 mg/kg bw/day

Remarks:

40 µmol BPS/kg gavage (Exp. 4)

Dose / conc.:

50 mg/kg bw/day

Remarks:

200 µmol/kg, gavage (Exp. 5)

No. of animals per sex per dose / concentration:

6 (Experiment 3 and 4), 4 (Experiment 5)

Control animals:

no

Details on study design:

Experiment 3: IV administrations of BPS and BPS-glucuronide at the respective doses of 20 µmol/kg and 2.23 µmol/kg in 6 piglets, 72 h apart
Experiment 4: 20 µmol/kg IV BPS administration of BPS followed by 40 µmol/kg BPS administration by orogastric gavage in 6 piglets, 72 h apart
Experiment 5: 20 µmol/kg IV administration of both BPA and BPS and 200 µmol/kg administration of both BPS and BPA by orogastric gavage in 4 piglets, 4 days apart

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, blood, plasma
- Time and frequency of sampling: before and after adminsitration (blood), at different times regularly spanned over 24 h after dosing (urine), centrifuged blood sample (plasma)
- Serial jugular venous plasma samples at 15 min, 30 min, and 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 h after BPS administration by IV route and orogastric gavage
- Total urine collected at 3, 6, 9, 12, 21, and 24 h after BPS administration by IV route and orogastric gavage

Details on absorption:

BPS oral absorption was near total (99.9%). Model predicitions revealed nearly 100% of the ingested BPS dose gained direct access to the liver, where the estimated hepatic first-pass effect was only 41%.

Details on distribution in tissues:

After oral administration, the BPS plasma concentrations increased to maximal values about 1 h and 30 minutes after dosing. Forty-one percent of the oral BPS dose reaching the portal blood was metabolized by the liver and contributed to the systemic exposure to BPS-glucuronide (41%), with 57.4% of the BPS oral dose being bioavailable.
The mean volume of the central compartement was 0.30 L/kg.

Details on excretion:

The mean fractional urinary excretion of BPS as BPS-glucuronide was 86.5 ± 23.9% after oral dosing. Renal clearance values were calculated with 0.00035 L/kg x h for BPS and 0.037% plasma clearance.
Unconjugated BPS in urine represented 0.027 ± 0.0084% of the intravenous BPS doses.

Test no.:

#1

Toxicokinetic parameters:

Cmax: 2.12 ± 1.82 µmol/L per µmol/kg bw

Remarks:

(IV dosing)

Test no.:

#1

Toxicokinetic parameters:

Tmax: not applicable

Remarks:

(IV dosing)

Test no.:

#1

Toxicokinetic parameters:

AUC: 1.11 ± 0.30 µmol x h/L per µmol/kg

Remarks:

(IV dosing)

Test no.:

#1

Toxicokinetic parameters:

other: Clearance: 0.95 ± 0.24 L/kg x h

Remarks:

(IV dosing)

Test no.:

#2

Toxicokinetic parameters:

Cmax: 0.51 ± 0.29 µmol/L per µmol/kg bw

Remarks:

(gavage)

Test no.:

#2

Toxicokinetic parameters:

Tmax: 0.53 ± 0.28 h

Remarks:

(gavage)

Test no.:

#2

Toxicokinetic parameters:

AUC: 0.63 ± 0.29 µmol x h/L per µmol/kg bw

Remarks:

(gavage)

Test no.:

#2

Toxicokinetic parameters:

other: Apparent clearance: 1.86 ± 0.73 L/kg x h

Remarks:

(gavage)

Metabolites identified:

yes

Details on metabolites:

BPS-glucuronide

Executive summary:

Experiments were conducted in piglets to evaluate the kinetics of BPA, BPS, and their glucuronoconjugated metabolites in plasma and urine after intravenous administration of BPA, BPS, and BPS glucuronide (BPSG) and gavage administration of BPA and BPS. A comprehensive NLME model was used to estimate the key TK parameters that drive the internal exposure to active compounds.

BPS’s oral absorption was near total (99%). After not beeing matabolized in the enterocytes, 41% of the absorbed BPS fraction underwent a hepatic first-pass glucuronidation. Therefore, the systemic bioavailability of BPS was 57.4%. Plasma clearance of BPS was 0.95 L/kg x h. Renal clearance value of 0.037% was negiligible in comparison with hapatic clearance. The mean fractional urinary excretion of BPS as BPS-glucuronide was 86.5 ± 23.9% after oral dosing. About half of the BPS doses were eliminated 3 h after dosing.

77% of the oral dose of BPA was absorbed and underwent an extensive first-pass glucuronidation either in the gut (44%) or in the liver (53%). Systemic bioavailability of BPA was calculated to be 0.50%.

Reference 5

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 for cross-reference:

reference to other study

Objective of study:

toxicokinetics

Qualifier:

according to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Version / remarks:

23 July, 2010

Deviations:

no

GLP compliance:

yes

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

Species:

rat

Strain:

Wistar

Remarks:

Crl:WI (Han)

Sex:

male/female

Details on test animals or test system 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

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

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 / concentration:

- 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.

Type:

other: Kinetics

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:

other: Parameters in Table 1

Remarks:

Toxicokinetic parameters are displayed in Table 1

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

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.

Description of key information

BASF SE, 2019: oral absorption in rats: 300 mg/kg bw (high dose): 93-96%; 30 mg/kg bw (low dose): 87-95%

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

BASF SE, 2019:

In a GLP-compliant OECD TG 417 study, the absorption, distribution, elimination and plasma kinetics of 14C-4,4'-sulphonyldiphenol in male and female Wistar rats after oral administration was evaluated.

For plasma kinetics, four animals per gender and dose group were treated with 14C-4,4'-sulphonyldiphenol and blood samples were taken in general from the vena saphena at the following time points: 1, 2, 4, 8, 24, 48, 72, 96, 120, 144 and 168 hours after oral dosing.

For mass balance, the animals were treated with 14C-4,4'-sulphonyldiphenol and urine was collected after 6, 12 and 24 hours and subsequently at 24- hour time intervals up to 168 hours and feces at 24-hour time intervals up to 168 hours.

In the low dose balance experiment (experiment 4), the first two male animals were placed in closed metabolism cages in order to additionally collect exhaled air for 48 hours to demonstrate that less than 2 % of the total radioactive dose were detected in exhaled air and to justify that balance experiments were carried out in open systems.

For experiments performed to investigate biliary excretion, bile ducts of animals were cannulated and six animals per gender and dose group were treated orally with 14C-4,4'-sulphonyldiphenol. After treatment, the animals were placed in metabolism cages, and bile was collected at 3 h intervals as well as urine and feces at 24 h intervals up to 72 h, depending on the health state of the animals and the bile flow.

For tissue distribution experiments, three animals per gender, dose group and time point were treated orally. To achieve information on a potential time-dependent decrease of radioactivity in blood, organs and tissues, animals were sacrificed at four different time points, which were selected based on the results of the plasmakinetic experiments (experiments 1 and 2) and corresponded to the time points of maximum plasma concentration (MPC), second MPC (due to assumed enterohepatic recirculation), 1/2 MPC and 1/4 MPC.

The concentrations of the radioactive residues in the target matrices were analysed by liquid scintillation counting after appropriate sample work-up.

Toxicokinetics:

In plasmakinetics, maximum plasma concentrations occurred 1 and 4 hours after oral administration of the high and low dose. The presence of two maxima in plasmakinetics may be explained by a potential enterohepatic recirculation. Radioactivity declined rapidly post dosing and mean concentration below loq were generally found 72 hours post dosing. The AUC values indicate a sex independent internal exposure. Increasing the dose by a factor of about 10 (from target dose level of 30 to 300 mg/kg bw) an increase of the AUC-values by a factor of about 14 for male and female animals was measured.

Taken together, plasmakinetics of 14C-4,4'-sulphonyldiphenol within the current study demonstrated high absorption, potential enterohepatic recirculation, fast excretion and a supra-linear correlation of the internal exposure to oral dose. A comparable time course of radioactivity was found for blood as for plasma in both sexes.

Excretion:

After single oral administration of 300 and 30 mg/kg bw of 14C-4,4'-sulphonyldiphenol as well as after daily administration for 14 days with unlabelled DHDPS followed by one oral dose of the labelled substance at 30 mg/kg bw, the recoveries ranged between 90% and 110% of the dose for all experiments.

Excretion via urine and feces predominantly occurs within the first 48 hours post exposure (>40%). The total amounts of excreted radioactivity reflected more than 90% of the administered dose for both genders. Neither gender- nor dose-dependent differences in excretion patterns were observed.

In a bile excretion study after bile duct catheterization, bile, urine and feces were collected up to 72 hours from rats which were dosed with 14C-4,4'-sulphonyldiphenol at 300 and 30 mg/kg bw.

Within 72 hours after administration of 14C-4,4'-sulphonyldiphenol at a dose level of 300 mg/kg bw, mean excretion via bile was found to be 43.81 % and 45.65 % of the administered radioactivity in males and females, respectively. Mean total excretion of radioactivity via urine after 72 hours was 47.52 % for males and 48.91 % for females. At the low dose level (30 mg/kg bw.), excretion via bile was found to be 56.39 % and 38.21 % of the administered radioactivity in males and females, respectively. Total excretion of radioactivity via urine after 72 hours was 37.72 % for males and 46.37 % for females.

Based on the amounts of radioactivity excreted via bile and urine, as well as the radioactive residues found in cage wash and carcass, the oral absorption of 14C-4,4'-sulphonyldiphenol in rats was calculated to be about 93 % and 96 % of the administered dose for males and females at a dose of 300 mg/kg bw as well as 95 % and 87 % of the administered dose for males and female rats at a dose level of 30 mg/kg bw, respectively.

Tissue distribution:

The highest tissue concentrations (means) 1 hour post dosing were found in the GI-tract, followed by liver and kidney in male rats and liver, kidney and thyroid in female rats. The lowest mean radioactive residues at this time point were brain, adipose tissue and bone in male animals and brain, bone, adipose tissue and muscle in female animals, respectively. For both sexes and both dose groups, the radioactive residue concentrations declined in organs and tissues from the 1 h time point on. However, the concentration in the carcass samples decreased slower than in other organs and tissues.

 

Taken together, 14C-4,4'-sulphonyldiphenol was rapidly absorbed from the gastrointestinal tract. Based on the bile excretion experiments, about 93 and 96 % of the administered dose were absorbed at a dose level of 300 mg/kg bw for male and female rats, respectively, whereas about 95% of the administered dose were absorbed for males and 87 % of the administered dose were absorbed for females at a dose level of 30 mg/kg. The excretion of radioactivity occurred mainly within two days after dosing, generally with a high excretion via urine and bile. Plasma kinetics confirmed high oral absorption and demonstrated potential enterohepatic recirculation, fast excretion and a slight supra-linear correlation of the internal exposure to the oral dose. Tissue distribution experiments showed generally sublinear correlation between radioactive residues in organs and tissues, but supralinear correlation between radioactive residues in carcass and the external dose.

 

 

Additional information:

Oral absorption:

Gayrard et al. (2019) investigated the oral absorption rate of BPS. Bisphenol S (BPS), a substitute for Bisphenol A (BPA), could have an increased endocrine disruptive risk based on its hormonal activity if oral availability and systemic persistency, or more general its toxicokinetic (TK) properties, were higher than TK properties of BPA.The TK behavior of BPA and BPS was investigated by administering the two compounds by intravenous and oral routes in piglet, a known valid model for investigating oral TK. Experiments were conducted in piglets to evaluate the kinetics of BPA, BPS, and their glucuronoconjugated metabolites in plasma and urine after intravenous administration of BPA, BPS, and BPS glucuronide (BPSG) and gavage administration of BPA and BPS. A population semi-physiologically based TK model describing the disposition of BPA and BPS and their glucuronides was built from these data to estimate the key TK parameters that drive the internal exposure to active compounds. BPS’s oral absorption was near total (99.9%). Forty-one percent of the oral BPS dose reaching the portal blood was metabolized by the liver and contributed to the systemic exposure to BPS-glucuronide (41%), with 57.4% of the BPS oral dose being bioavailable. The mean fractional urinary excretion of BPS as BPS-glucuronide was 86.5 ± 23.9% after oral dosing. About half of the BPS doses were eliminated 3 h after dosing.

 

Waidyanatha et al. (2018) investigated the disposition and metabolism of BPS in mice following gavage and intravenous administration. In male rats following gavage administration of 150 mg/kg [14C]BPS the main route of excretion was via urine (70%) and the feces (12%) The disposition was similar in female mice following gavage administration (67% and 17%, respectively). Radioactivity remaining in tissues at 72 h in both sexes was≤0.19%. Following an intravenous dose of 50 mg/kg [14C]BPS in male mice, the pattern of excretion was similar to gavage (urine 68%,feces 18%, tissues 0.13%).

These data suggest that the dose excreted in feces following gavage administration is likely the absorbed dose. Urinary metabolites included the glucuronide and sulfate conjugates with a moderate amount of parent.

BPS was well absorbed following oral exposure in mice and extensively excreted with minimal tissue retention.

 

Inhalation absorption:

Due to the negligible vapor pressure inhalation as a vapor can be excluded. At room temperature 4,4'-sulphonyldiphenol is a crystalline powder and approx. 60% of the particles are less than 100 µm in size, and approx. 2% of the particles are less than 10 µm in size (Granulometry; BASF AG, 2009). Therefore it can be anticipated, that a major fraction of the 4,4'-sulphonyldiphenol powder can be inhaled, though only a very small fraction can reach the alveolar region of the respiratory tract.

Based on these considerations it can be anticipated, that most of the inhalable particulate dust will deposit in the upper thoracic region of the respiratory tract. Due to the mucocilliary transport in this region of the lung, an effective clearance of particulate matter from the respiratory tract takes place (within hours). Due to the rather low water solubility of 4,4'-sulphonyldiphenol it is likely that most of the inhaled substance is removed from the respiratory tract ahead of being solubilized in the mucus lining of the respiratory tract. The small fraction depositing in the alveolar region would mainly be engulfed by alveolar macrophages and translocated to the ciliated airways. Based on these considerations is can be extrapolated that most of the systemic absorption of inhaled 4,4'-sulphonyldiphenol is due to oral cross-contamination. Systemic uptake in the respiratory tract is therefore presumably limited to very low amounts of particles carried into the pulmonary interstitium and lymphoid tissues of the alveoli and dissolved into the mucus lining of the upper and thoracic regions. The phenomenon of respiratory overload, resulting in a saturation of the clearance is included in the rational for the OEL (MAK-value) for inert dusts.

 

Dermal absorption:

Dermal absorption represents the amount of topically applied test substance that is found in the epidermis (stratum corneum excluded) and in the dermis, and this quantity is therefore taken as systemically available.

Dry particulates first have to dissolve into the surface moisture of the skin before uptake may occur. Due to the rather low water solubility of 1.1 g/l (at 20°C) it can be anticipated that 4,4'-sulphonyldiphenol is dissolving to only a minor amount. The potential for dermal permeation of dissolved substances is mainly dependent on the molecular weight and the Pow. This can be predicted by in silico equations (e.g. DERMWIN v2.00). For 4,4'-sulphonyldiphenol with a molecular weight of 250.27 g/mol and a log Pow of 1.2 the dermal permeability coefficient (Kp) was calculated as 0.000387 cm/hr indicating a very low dermal uptake. Such calculations can of course only extrapolate a realistic dermal permeation. In case of 4,4'-sulphonyldiphenol the absence of systemic toxicity in an acute dermal toxicity study with guinea pigs is further substantiating this extrapolation, even though the reliability of the assay is limited (Eastman Kodak, 1983).

Summarized, a low rate of dermal absorption can be anticipated based on the predicted low solubility in the surface moisture and the low dermal permeability.

Additionally, dermal absorption was examined ex vivo. Split-thickness human skin membranes were mounted into static diffusion cells. Receptor fluid was added to the receptor chamber (nominal volume 5 mL, nominal exposure are 0.64 cm²). The test preparations were applied (500 µL/cm² or 10 µL/cm²) to human split-thickness skin membranes and the cells were left open to the atmosphere. The concentration of the test substance in the test preparations was 200 mg/L for infinite dose and 100 mg/L for finite dose applications. Percutaneous absorption was assessed by collecting receptor fluid samples prior to dosing and at 1, 2, 4, 8, 12 and 24 h post dose. At 8 h post dose, the exposure period was terminated by removing the applied test preparation from the skin surface (where applicable) and washing the skin surface with a concentrated commercial hand wash soap followed by rinsing with a dilute soap solution (2 %, v/v) and drying the surface with a tissue swab. At 24 h post dose, the skin was removed from the static cells, the stratum corneum tape stripped and the skin divided into epidermis, dermis and unexposed skin samples. The skin samples were dissolved with Solvable tissue solubiliser. All samples were analysed by liquid scintillation counting. Following topical (infinite dose) application of 200 mg/L test preparation to human skin, the absorbed dose was 0.08 +/- 0.08 % (0.08 +/- 0.08 µg equiv./cm²) of the applied dose. The dermal delivery was 0.56 +/- 0.19 % (0.57 +/- 0.20 µg equiv./cm²) of the applied dose. The potentially absorbed dose was 1.80 +/- 0.38 % (1.84 +/- 0.39 µg eqiv./cm²) of the applied dose. The mass balance was 100.26 +/- 0.26 % (102 +/- 0.26 µg equiv./cm²) of the applied dose. Following topical (finite dose) application of 100 mg/L to human skin, the absorbed dose was 0.19 +/- 0.21 % (1.94 +/- 2.15 ng equiv./cm²) of the applied dose. The dermal delivery was 1.66 +/- 1.00 % (17.2 +/- 10.3 ng equiv./cm²) of the applied dose. The potentially absorbed dose was 8.79 +/- 3.24 % (90.8 +/- 33.4 ng equiv./cm²) of the applied dose. The mass balance was 100.40 +/- 0.96 % (1037 +/- 9.87 ng equiv./cm²) of the applied dose. (European Thermal Paper Association, 2017) .

A study with 6 human volunteers confirms the low bioavailabilty of BPS after dermal exposure. Khmiri et al. 2020 treated 6 females with 1 mg/kg bw BPS for 6 hours. The individual time courses of BPS-d8 and BPSG-d8 in plasma over a 48-h period following the onset of a 6-h cutaneous application of 1 mg/kg bw of BPS-d8 in volunteers showed values below the lower limit of quantification (LLOQ) for most time points such that average time course were not reported. The low levels did not allow to determine toxicokinetic parameters. 

Nevertheless, an increase in plasma levels of both compounds was detectable from individual profiles. Peak values were reached between 5 and 8 hours after application. BPSG-d8 was found in higher molar concentrations than BPS-d8 (2- to 9-fold at peak levels).

Limited amounts of BPS-d8 and its conjugate were recovered in urine. Peak excretion was reached between 5 and 11 hours postdosing. BPSG-d8 is excreted slower than BPS-d8 over the 72h collection period, however levels were close to the LLOQ, thus the results have to be considered with caution. The cumulative excretion time courses of BPS-d8 and BPSG-d8 show that BPSG-d8 is excreted in about 20-times higher amounts than BPS-d8, and that excretion is not totally complete after 72 h (lack of asymptote)  for part of the volunteers.

The average percent (±SD) of the administered dose recovered in urine as BPS-d8 and BPSG-d8 was about 0.004 ± 0.003 and 0.09 ± 0.07%, respectively. This suggests a rather low relative bioavailability by the cutaneous route when compared to the oral route.