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EC number: 405-520-5 | CAS number: 95235-30-6 D-8; DD-8
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Link to relevant study record(s)
- Endpoint:
- basic toxicokinetics, other
- Type of information:
- other: Expert Statement
- Adequacy of study:
- key study
- Study period:
- 2019-05-23
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Expert Statement
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Expert Statement
- GLP compliance:
- not specified
- Details on absorption:
- Absorption is a function of the potential for a substance to diffuse across biological membranes. Generally, absorption is favored for molecular weights below 500 g/mol and log Pow values between -1 and 4. Therefore, it can be concluded that D-8 is likely to become bioavailable following the oral route, as indicated by its physicochemical properties. This assumption is confirmed by the results of repeated dose toxicity studies, where clinical signs were observed indicating systemic bioavailability.
Absorption via the respiratory route also depends on physico-chemical properties like vapor pressure, log Pow and water solubility. In general, highly volatile substances are those with a vapor pressure greater than 25 kPa or boiling point below 50°C. Substances with log Pow values between -1 and 4 are favored for absorption directly across the respiratory tract epithelium by passive diffusion. Due to its low vapor pressure of < 1.0E-05 Pa at 27 °C D-8 is unlikely to be available as a vapor under normal use conditions. Therefore, exposure and uptake via inhalation is considered as negligible.
In general, dermal absorption is favored by log Pow values between 1 and 4, particularly if water solubility is high. As the water solubility is quite low, dermal uptake for D-8 is expected to be moderate. This is confirmed by the results of the acute dermal study where the compound did neither induce local nor systemic effects in rats and rabbits. - Details on distribution in tissues:
- In general, the smaller the molecule, the wider the distribution. Small water-soluble molecules will diffuse through aqueous pores. If the molecule is lipophilic (log P > 0) it is likely to distribute into cells and the intracellular concentration may be higher compared to its extracellular concentration. D-8 absorbed by the body, following either oral consumption or passage through the skin, will distribute by systemic circulation. Based on the compound’s physical-chemical characteristics, particularly water solubility and octanol-water partition coefficient, bioaccumulation is not likely to occur.
- Details on excretion:
- In general, urinary excretion in favored by low molecular weight (below 300 g/mol in the rat) good water solubility, and ionization of the molecule. Substances that are excreted in the bile tend to have higher molecular weights or may be conjugated as glucuronides derivates. Therefore, D-8 is expected to be excreted partially via urine but also via faeces.
- Metabolites identified:
- yes
- Details on metabolites:
- Assessment of abiotic degradation over a range of pH-values showed that D-8 is not likely to hydrolyse under acidic, basic or neutral pH conditions. Thus, following possible absorption, formation of hydrolysis products in the body is unlikely. Metabolic transformation of D-8 may occur in the liver and may partially be catalysed by cytochrom P-450 enzymes. Phase II reactions may include sulfatation and glucuronidation as well as other conjugation reactions. It is likely that metabolism of D-8 will render the molecule more polar, leading to faster excretion via urine and bile (following conjugation). Most probably metabolism will not render the parent compound more toxic. This assumption is supported by results obtained in the Ames test and the HPRT test. The assays show that there is no significant difference in toxicity, in absence or presence of a rodent microsomal S9-fraction. This indicates that the formation of reactive metabolites is rather unlikely. The metabolism of D-8 and six other derivatives was investigated in hepatocytes using high resolution liquid chromatography coupled with mass spectrometry (Waidyanatha et al., 2018). To assess metabolite formation, incubations were performed in triplicate using male rat, mouse and human hepatocytes with 1 or 10 µM D-8 in a 37 °C incubator with 5% CO2 atmosphere and gentle shaking. Concurrent with hepatocyte incubations, a similar incubation was conducted using 1 mL incubation media only (no hepatocytes) to assess analyte losses over the duration of the experiment; this incubation was treated exactly as for the cell incubations. At termination (300 min) the entire sample was removed, added to microcentrifuge tubes containing 1 mL acetonitrile and vortexed. Samples were centrifuged (11,000g for 1 min) and supernatants were analysed. As a result, D-8 gave parent substance, hydroxylated compound, glucuronide, sulfate, and sulfate conjugate of a hydroxylated compound similar to BPS. With D-8, hydroxylated parent and sulfated parent showed two peaks suggesting presence of multiple hydroxylated products. Bisphenol S (BPS) as a metabolite of D-8 is formed but at very low levels. Only male and female human hepatocytes generated BPS concentrations that rose above LOQ (1 ng/mL). However, only 0.53-1.27% of the exposure concentration (1 µM D-8) is metabolized to BPS in female hepatocytes. In male hepatocytes, only up to 0.64% of D-8 is metabolized to BPS.
- Conclusions:
- Based on physico-chemical properties, oral absorption and distribution through-out the body is expected. Dermal absorption is expected to be low. These assumptions are further supported by the results of the oral and acute dermal toxicity studies as well as the skin irritation study. Absorption via the inhalation route is, due to physico-chemical properties of the test item, not expected. Bioaccumulation of the substance is not expected after continuous exposure. The test substance is expected to be excreted via faeces and urine.
- Executive summary:
4-hydroxy-4'-isopropoxydiphenyl sulfone is a white, odourless powder at ambient conditions with a molecular weight of 292.3 g/mol. The test item has a water solubility of 19.7 mg/L. The log Pow is determined to be 3.36 at 25°C and the vapour pressure is< 1.0E-05 Pa at 27 °C.
Absorption
Absorption is a function of the potential for a substance to diffuse across biological membranes. Generally, absorption is favored for molecular weights below 500 g/mol and log Pow values between -1 and 4. Therefore, it can be concluded that D-8 is likely to become bioavailable following the oral route, as indicated by its physicochemical properties. This assumption is confirmed by the results of repeated dose toxicity studies, where clinical signs were observed indicating systemic bioavailability.
Absorption via the respiratory route also depends on physico-chemical properties like vapor pressure, log Pow and water solubility. In general, highly volatile substances are those with a vapor pressure greater than 25 kPa or boiling point below 50°C. Substances with log Pow values between -1 and 4 are favored for absorption directly across the respiratory tract epithelium by passive diffusion. Due to its low vapor pressure of < 1.0E-05 Pa at 27 °C D-8 is unlikely to be available as a vapor under normal use conditions. Therefore, exposure and uptake via inhalation is considered as negligible.
In general, dermal absorption is favored by log Pow values between 1 and 4, particularly if water solubility is high. As the water solubility is quite low, dermal uptake for D-8 is expected to be moderate. This is confirmed by the results of the acute dermal study where the compound did neither induce local nor systemic effects in rats and rabbits.
Distribution
In general, the smaller the molecule, the wider the distribution. Small water-soluble molecules will diffuse through aqueous pores. If the molecule is lipophilic (log P > 0) it is likely to distribute into cells and the intracellular concentration may be higher compared to its extracellular concentration. D-8 absorbed by the body, following either oral consumption or passage through the skin, will distribute by systemic circulation. Based on the compound’s physical-chemical characteristics, particularly water solubility and octanol-water partition coefficient, bioaccumulation is not likely to occur.
Metabolism
Assessment of abiotic degradation over a range of pH-values showed that D-8 is not likely to hydrolyse under acidic, basic or neutral pH conditions. Thus, following possible absorption, formation of hydrolysis products in the body is unlikely. Metabolic transformation of D-8 may occur in the liver and may partially be catalysed by cytochrom P-450 enzymes. Phase II reactions may include sulfatation and glucuronidation as well as other conjugation reactions. It is likely that metabolism of D-8 will render the molecule more polar, leading to faster excretion via urine and bile (following conjugation). Most probably metabolism will not render the parent compound more toxic. This assumption is supported by results obtained in the Ames test and the HPRT test. The assays show that there is no significant difference in toxicity, in absence or presence of a rodent microsomal S9-fraction. This indicates that the formation of reactive metabolites is rather unlikely. The metabolism of D-8 and six other derivatives was investigated in hepatocytes using high resolution liquid chromatography coupled with mass spectrometry (Waidyanatha et al., 2018). To assess metabolite formation, incubations were performed in triplicate using male rat, mouse and human hepatocytes with 1 or 10 µM D-8 in a 37 °C incubator with 5% CO2 atmosphere and gentle shaking. Concurrent with hepatocyte incubations, a similar incubation was conducted using 1 mL incubation media only (no hepatocytes) to assess analyte losses over the duration of the experiment; this incubation was treated exactly as for the cell incubations. At termination (300 min) the entire sample was removed, added to microcentrifuge tubes containing 1 mL acetonitrile and vortexed. Samples were centrifuged (11,000g for 1 min) and supernatants were analysed. As a result, D-8 gave parent substance, hydroxylated compound, glucuronide, sulfate, and sulfate conjugate of a hydroxylated compound similar to BPS. With D-8, hydroxylated parent and sulfated parent showed two peaks suggesting presence of multiple hydroxylated products. Bisphenol S (BPS) as a metabolite of D-8 is formed but at very low levels. Only male and female human hepatocytes generated BPS concentrations that rose above LOQ (1 ng/mL). However, only 0.53-1.27% of the exposure concentration (1 µM D-8) is metabolized to BPS in female hepatocytes. In male hepatocytes, only up to 0.64% of D-8 is metabolized to BPS.
Excretion
In general, urinary excretion in favored by low molecular weight (below 300 g/mol in the rat) good water solubility, and ionization of the molecule. Substances that are excreted in the bile tend to have higher molecular weights or may be conjugated as glucuronides derivates. Therefore, D-8 is expected to be excreted partially via urine but also via faeces.
References
ECHA (2017), Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance, Version 3.0, June 2017
Marquardt H., Schäfer S. (2004). Toxicology. Academic Press, San Diego, USA, 2nd Edition 688-689.
Waidyanatha et al. 2018: Disposition and metabolism of the bisphenol analogue, bisphenol S, in H) Harlan Sprague Dawley rats and B6C3F1/N mice and in vitro in hepatocytes from rats, mice, and humans, Toxicology and Applied Pharmacology 351 (2018) 32-45; Additional information on metabolites: https://tools.niehs.nih.gov/cebs3/views/?action=main.dataReview&bin_id=3391
- Endpoint:
- basic toxicokinetics in vitro / ex 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:
- metabolism
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- The clearance and metabolism of D-8 and six other derivatives were investigated in hepatocytes from rats, mice and humans using high resolution liquid chromatography coupled with mass spectrometry (LC-MS).
- GLP compliance:
- no
- Specific details on test material used for the study:
- - purity : 99.5%
- Radiolabelling:
- no
- Details on study design:
- The clearance and metabolism of D-8 were investigated in male or female human, B6C3F1 mouse and Sprague Dawley (SD) rat hepatocytes.
- Details on dosing and sampling:
- METABOLITE CHARACTERISATION STUDIES
- Time and frequency of sampling: after 300 min incubation of test material on cells
- Method type for identification: LC-MS/MS
- Limits of detection and quantification: 0.004 µM (1 ng/mL)
DETAILS ON CELLS
Human:
Human male (Caucasian, 20-47 years of age, n = 6) and female (Caucasian, 22-57 years of age, n = 6) hepatocytes pools (CryostaX™) were from Xenotech LLC (Lenexa, KS). Tubes of cells were removed from cryogenic storage, and were immediately dispensed into 50-mL pre-warmed OptiThaw Hepatocyte Media (K8000) and gently inverted until all the pellets were melted. The hepatocyte suspensions were centrifuged at 100g for 5 min, the supernatant was aspirated without disturbing the cell pellet and the cell pellet was resuspended with Optilncubate Hepatocyte Media (K8400). A 50-µL aliquot of the homogenous cell suspension was transferred to a counting tube containing Trypan Blue. The cell concentration determined at the time of use in studies were >0.523 x 10E6 cells/mL and the viability was between 62 and 86%.
Rat /Mice:
Male (n = 4, lot RSD202) and female (n = 8, lot RSD297) SD rat (9-12 weeks old) and male (n = 8, lot MXX107) and female (n = 10, MXX 109) B6C3F1 mouse (6 weeks old) hepatocyte pools were obtained from Triangle Research Laboratories (RTP, NC). Hepatocytes were removed from cryogenic storage and placed in a 37°C water bath. Once thawed, the cells were transferred to a 50-mL centrifuge tube containing a Percoll® thawing media (MCRT50). The original vial was rinsed with thawing media and the rinsate was added to the 50-mL tube and then it was centrifuged for 10min at 100g. The supernatant was removed and for every 1 x 10E6 total cells expected, ~1 mL of maintenance media (MM250) was added to the cell pellet and the cells were resuspended. A 100-µL of resuspended cell aliquot was removed and transferred to a counting tube containing Trypan Blue. The cell concentration determined at the time of use in studies were ≥0.407 x 10E6 and ≥0.620 x 10E6 cells/mL for rats and mice hepatocytes, respectively; the corresponding viability was ≥73.5% for rats and ≥78.8% for mice.
INCUBATIONS
Incubations to determine clearance were performed at 1 µM final concentration. Incubations were performed in triplicate in each male and female rat, mouse, and human hepatocytes with 1 mL cell suspension in 24-well polystyrene cell culture plates in a 37 °C incubator with 5% CO2 atmosphere and gentle shaking. Each test material was prepared at 0.1 mM in acetonitrile and added to wells so that the final concentration of acetonitrile in the incubation was 1%. Concurrent with hepatocyte incubations, incubation was conducted using 1 mL incubation media only (no hepatocytes) to assess analyte losses over the duration of the experiment; this incubation was treated exactly as for the cell incubations. Following the addition of the test material, aliquots (50 µL) were removed from the incubation at 0, 15, 30, 45, 60, 120, 180 and 300 min and added to 150 µL acetonitrile containing BPA as the internal standard (IS) (500 ng/mL for all except D90 where it was 50 ng/mL). Each sample was vortexed and centrifuged (11,000g for 1 min) to pellet cell debris and proteins, and supernatants were stored at -70°C until analysis.
To assess metabolite formation, incubations were performed in triplicate using male rat, mouse and human hepatocytes with 1 mL cell suspension in 24-well polystyrene cell culture plates with 10 µM D-8 in a 37 °C incubator with 5% CO2 atmosphere and gentle shaking. Concurrent with hepatocyte incubations, a similar incubation was conducted using 1 mL incubation media only (no hepatocytes) to assess analyte losses over the duration of the experiment; this incubation was treated exactly as for the cell incubations. At termination (300 min) the entire sample was removed, added to microcentrifuge tubes containing 1 mL acetonitrile and vortexed. Samples were centrifuged (11,000g for 1 min) and supernatants were transferred to vials and stored at -70°C until analysis. - Details on excretion:
- In general, human hepatocytes cleared BPS and derivatives slower than rodents. In all species, clearance of 2,4-BPS was higher than BPS. Of the derivatives examined, the clearance of BPS-MPE, BPS-MAE, 2,4-BPS and TGSA were similar to each other and were the highest and the clearance of D-8 and BPS were lower and close to each other (see table 1).
- Metabolites identified:
- yes
- Details on metabolites:
- D-8 gave parent, hydroxylated compound, glucuronide, sulfate, and sulfate conjugate of a hydroxylated compound similar to BPS. With D-8, hydroxylated parent and sulfated parent showed two peaks suggesting presence of multiple hydroxylated products. Bisphenol S (BPS) as a metabolite of D-8 is formed but at very low levels. An example for the quantity of BPS formed after incubation of hepatocytes with D-8 is shown in the attachment. The limit of quantitation (LOQ) for BPS was 1 ng/mL (0.004 μM), and much of the data generated in these incubations were at or below LOQ, in male and female mouse, and male and female rat. Only the male and female human hepatocytes generated BPS concentrations that rose above LOQ. However, only 0.53-1.27% of the exposure concentration (here 1 µM D-8) is metabolized to BPS in female hepatocytes. In male hepatocytes, only up to 0.64% of D-8 is metabolised to BPS.
- Conclusions:
- The clearance and metabolism of bisphenol S (4,4’-BPS or BPS, CAS 80-09-1) and six derivatives including D-8 were investigated in hepatocytes from rats, mice and humans using high resolution liquid chromatography coupled with mass spectrometry (LC-MS). D-8 gave parent, hydroxylated compound, glucuronide, sulfate, and sulfate conjugate of a hydroxylated compound similar to BPS. With D-8, hydroxylated parent and sulfated parent showed two peaks suggesting presence of multiple hydroxylated products. Bisphenol S (BPS) as a metabolite of D-8 is formed but at very low levels and only in human hepatocytes. In general, human hepatocytes cleared BPS and derivatives slower than rodents.
Referenceopen allclose all
Table 1: Clearance and half-life of BPS and derivatives in rat mouse, and human hepatocytes in vitro
Chemical |
Species |
Sex |
T 1/2 |
Clearance |
Abbreviation* |
|
|
[h] |
mL/(min*kg) |
BPS |
Rat |
Male |
1.002 (0.040) |
115.7 (4.6) |
|
|
Female |
0.486 (0.020) |
155.3 (6.4) |
|
Mouse |
Male |
0.488 (0.070) |
139.9 (21.4) |
|
|
Female |
0.581 (0.027) |
131.0(6.0) |
|
Human |
Male |
1.617(0.069) |
34.3(1.5) |
|
|
Female |
1.414(0.057) |
35.6(1.4) |
2.4-BPS |
Rat |
Male |
0.401 (0.030) |
289.5 (21 3) |
|
|
Female |
0.306 (0.006) |
246.8 (4.5) |
|
Mouse |
Male |
0.181 (0.013) |
373.6(28.4) |
|
|
Female |
0.212 (0.025) |
362.6 (46.5) |
|
Human |
Male |
0.458 (0.037) |
121.3 (10.1) |
|
|
Female |
0.311 (0.010) |
162.0 (5.1) |
BPS-MAE |
Rai |
Male |
0.246 (0.034) |
476.5 (65.0) |
|
|
Female |
0.114(0.010) |
664.0 (62.9) |
|
Mouse |
Male |
0.275 (0.044) |
249.1 (36.6) |
|
|
Female |
0.264 (0.017) |
288.2(19.0) |
|
Human |
Male |
0.750 (0.040) |
73.9 (4.0) |
|
|
Female |
0.639 (0.163) |
82.7 (23.4) |
D8 |
Rat |
Male |
0 598 (0.070) |
195.7(24.4) |
|
|
Female |
0.305 (0.017) |
247.7(13.8) |
|
Mouse |
Male |
0.486 (0.048) |
139.3 (13.6) |
|
|
Female |
0.425 (0.031) |
179.5(13.1) |
|
Human |
Male |
1.308 (0.052) |
42.3(1.7) |
|
|
Female |
0.667 (0.046) |
75.6(5.1) |
TGSA |
Rat |
Male |
0.490(0.193) |
263.7(107.0) |
|
|
Female |
0.278 (0.006) |
271.8(6.2) |
|
Mouse |
Male |
0.189(0.037) |
365.2 (73.8) |
|
|
Female |
0.285 (0.028) |
268.2(27.4) |
|
Human |
Male |
0.847 (0.0 14) |
65.3 (1.1) |
|
|
Female |
0.503 (0.026) |
100.2(5.4) |
BPS-MPE |
Rat |
Male |
0.209 (0.028) |
560.9 (70.8) |
|
|
Female |
0.152 (0.005) |
497.5(16.0) |
|
Mouse |
Male |
0.278 (0.017) |
242.8(15.2) |
|
|
Female |
0.265 (0.024) |
288.1 (25.3) |
|
Human |
Male |
0.442 (0.054) |
126.6(16.7) |
|
|
Female |
0.420(0.037) |
120.5(11.1) |
D90 |
Rat |
Male |
4.407 (0.858) |
26.9 (4.7) |
|
|
Female |
6.598 (2.220) |
12.2 (3.4) |
|
Mouse |
Male |
4.028 (0.815) |
17.2 (3.9) |
|
|
Female |
3.078 (0.306) |
24.9 (2.4) |
|
Human |
Male |
10.051 (7.272) |
7.4 (3.9) |
|
|
Female |
9.272 (2.690) |
5.7(1.5) |
a Average and (SD) for n=3 replicates are shown.
*BPS: bisphenol S
2.4-BPS: 2.4-bisphenol S
BPS-MAE. Bis(4 hydroxyphenyl)sulfonylphenyl
D8: 4-Hydroxy-4´isopropoxydiphenylsulfone
TGSA: 4.4´Sulfonylbis[2-(2-propenyl)]phenol
BPS-MPE: 4-Benzyloxyphenyl-4-hydroxyphenyl sulfone
D90: Bis(2-chloroethyl)ether-4.4-dihydroxydiphenyl sulfone copolymer
Description of key information
Based on physico-chemical properties, oral absorption and distribution through-out the body is expected. Dermal absorption is expected to be low.These assumptions are further supported by the results of the oral and acute dermal toxicity studies as well as the skin irritation study. Absorption via the inhalation route is, due to physico-chemical properties of the test item, not expected. Incubations of D-8 on human hepatocytes revealed the following metabolites: hydroxylated compound, glucuronide, sulfate, and sulfate conjugate of a hydroxylated compound similar to BPS. Bisphenol S (BPS) as a metabolite of D-8 is formed but only at very low levels (max. 1.3% of exposure concentration). Bioaccumulation of the substance is not expected after continuous exposure. The test substance is expected to be excreted via faeces and urine.
Key value for chemical safety assessment
- Bioaccumulation potential:
- no bioaccumulation potential
Additional information
4-hydroxy-4'-isopropoxydiphenyl sulfone is a white, odourless powder at ambient conditions with a molecular weight of 292.3 g/mol. The test item has a water solubility of 19.7 mg/L. The log Pow is determined to be 3.36 at 25°C and the vapour pressure is< 1.0E-05 Pa at 27 °C.
Absorption
Absorption is a function of the potential for a substance to diffuse across biological membranes. Generally, absorption is favored for molecular weights below 500 g/mol and log Pow values between -1 and 4. Therefore, it can be concluded that D-8 is likely to become bioavailable following the oral route, as indicated by its physicochemical properties. This assumption is confirmed by the results of repeated dose toxicity studies, where clinical signs were observed indicating systemic bioavailability.
Absorption via the respiratory route also depends on physico-chemical properties like vapor pressure, log Pow and water solubility. In general, highly volatile substances are those with a vapor pressure greater than 25 kPa or boiling point below 50°C. Substances with log Pow values between -1 and 4 are favored for absorption directly across the respiratory tract epithelium by passive diffusion. Due to its low vapor pressure of < 1.0E-05 Pa at 27 °C D-8 is unlikely to be available as a vapor under normal use conditions. Therefore, exposure and uptake via inhalation is considered as negligible.
In general, dermal absorption is favored by log Pow values between 1 and 4, particularly if water solubility is high. As the water solubility is quite low, dermal uptake for D-8 is expected to be moderate. This is confirmed by the results of the acute dermal study where the compound did neither induce local nor systemic effects in rats and rabbits.
Distribution
In general, the smaller the molecule, the wider the distribution. Small water-soluble molecules will diffuse through aqueous pores. If the molecule is lipophilic (log P > 0) it is likely to distribute into cells and the intracellular concentration may be higher compared to its extracellular concentration. D-8 absorbed by the body, following either oral consumption or passage through the skin, will distribute by systemic circulation. Based on the compound’s physical-chemical characteristics, particularly water solubility and octanol-water partition coefficient, bioaccumulation is not likely to occur.
Metabolism
Assessment of abiotic degradation over a range of pH-values showed that D-8 is not likely to hydrolyse under acidic, basic or neutral pH conditions. Thus, following possible absorption, formation of hydrolysis products in the body is unlikely. Metabolic transformation of D-8 may occur in the liver and may partially be catalysed by cytochrom P-450 enzymes. Phase II reactions may include sulfatation and glucuronidation as well as other conjugation reactions. It is likely that metabolism of D-8 will render the molecule more polar, leading to faster excretion via urine and bile (following conjugation). Most probably metabolism will not render the parent compound more toxic. This assumption is supported by results obtained in the Ames test and the HPRT test. The assays show that there is no significant difference in toxicity, in absence or presence of a rodent microsomal S9-fraction. This indicates that the formation of reactive metabolites is rather unlikely.
The metabolism of D-8 and six other derivatives was investigated in hepatocytes using high resolution liquid chromatography coupled with mass spectrometry (Waidyanatha et al., 2018). To assess metabolite formation, incubations were performed in triplicate using male rat, mouse and human hepatocytes with 1 mL cell suspension in 24-well polystyrene cell culture plates with 1 or 10 µM D-8 in a 37 °C incubator with 5% CO2 atmosphere and gentle shaking. Concurrent with hepatocyte incubations, a similar incubation was conducted using 1 mL incubation media only (no hepatocytes) to assess analyte losses over the duration of the experiment; this incubation was treated exactly as for the cell incubations. At termination (300 min) the entire sample was removed, added to microcentrifuge tubes containing 1 mL acetonitrile and vortexed. Samples were centrifuged (11,000g for 1 min) and supernatants were analysed. As a result, D-8 gave parent substance, hydroxylated compound, glucuronide, sulfate, and sulfate conjugate of a hydroxylated compound similar to BPS. With D-8, hydroxylated parent and sulfated parent showed two peaks suggesting presence of multiple hydroxylated products. Bisphenol S (BPS) as a metabolite of D-8 is formed but at very low levels. Only male and female human hepatocytes generated BPS concentrations that rose above LOQ (1 ng/mL). However, only 0.53-1.27% of the exposure concentration (1 µM D-8) is metabolized to BPS in female hepatocytes. In male hepatocytes, only up to 0.64% of D-8 is metabolized to BPS.
Excretion
In general, urinary excretion in favored by low molecular weight (below 300 g/mol in the rat) good water solubility, and ionization of the molecule. Substances that are excreted in the bile tend to have higher molecular weights or may be conjugated as glucuronides or glutathione derivates. Therefore, D-8 is expected to be excreted partially via urine but also via faeces.
Conclusion
Based on physico-chemical properties, oral absorption and distribution through-out the body is expected. Dermal absorption is expected to be low.These assumptions are further supported by the results of the oral and acute dermal toxicity studies as well as the skin irritation study.Absorption via the inhalation route is, due to physico-chemical properties of the test item, not expected. Incubations of D-8 on human hepatocytes revealed the following metabolites: hydroxylated compound, glucuronide, sulfate, and sulfate conjugate of a hydroxylated compound similar to BPS. Bisphenol S (BPS) as a metabolite of D-8 is formed but only at very low levels (max. 1.3% of exposure concentration). Bioaccumulation of the substance is not expected after continuous exposure. The test substance is expected to be excreted via faeces and urine.
References
ECHA (2017), Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance, Version 3.0, June 2017
Marquardt H., Schäfer S. (2004). Toxicology. Academic Press, San Diego, USA, 2nd Edition 688-689.
Waidyanatha et al. 2018: Disposition and metabolism of the bisphenol analogue, bisphenol S, in H) Harlan Sprague Dawley rats and B6C3F1/N mice and in vitro in hepatocytes from rats, mice, and humans, Toxicology and Applied Pharmacology 351 (2018) 32-45; Additional information on metabolites: https://tools.niehs.nih.gov/cebs3/views/?action=main.dataReview&bin_id=3391
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