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Diss Factsheets

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

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

Data source

Reference
Reference Type:
other: Expert Statement
Title:
Unnamed
Year:
2020
Report date:
2020

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Expert Statement
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
4-(4-isopropoxyphenylsulfonyl)phenol
EC Number:
405-520-5
EC Name:
4-(4-isopropoxyphenylsulfonyl)phenol
Cas Number:
95235-30-6
Molecular formula:
C15H16SO4
IUPAC Name:
4-[4-(propan-2-yloxy)benzenesulfonyl]phenol

Results and discussion

Toxicokinetic / pharmacokinetic studies

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.

Metabolite characterisation studies

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.

Applicant's summary and conclusion

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