Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

There is no specific requirement to generate experimental data on toxicokinetics in REACH. Annex I, Section 1.0.2 states that “the human health hazard assessment shall consider the toxicokinetic profile (i.e. absorption, metabolism, distribution and elimination) of the substance”. Furthermore, REACh announces in Annex VIII (Section 8.8.1) that one should perform an “assessment of the toxicokinetic behaviour of the substance to the extent that can be derived from the relevant available information”.

In the final decision on substance evaluation pursuant to article 46(1) of Regulation (EC) No 1907/2006 for 4,4'-sulfonyldiphenol (CAS 80-09-1; EC 201-250-5) ECHA has stated that the Registrants are requested to carry out Toxicokinetics

(test method: EU B.36/OECD 417). Results of the study will be reported in a dossier update as soon as all the results and the final report will be available.

Absorption:

oral

From the molecular weight of 250.27 g/mol, the log Pow of 1.2 and the water solubility of 1.1 g/l (at 20°C) absorption in the GI-tract needs to be anticipated. This assumption is substantiated by the observed systemic toxicity in repeated dose toxicity studies (e.g. Office of Environmental Chemicals Safety Environmental Health Bureau, 1999).

 

Inhalation:

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:

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)

 

Accumulative potential

Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, substances with high log P values tend to have longer half-lives unless their large volume of distribution is counter-balanced by a high clearance. On this basis, there is the potential for highly lipophilic substances (log P >4) to accumulate in individuals that are frequently exposed (e.g. daily at work) to that substance. Since for 4,4'-sulphonyldiphenol the log Pow is 1.2 no significant accumulative potential in adipose tissue needs to be anticipated. In addition, the very low BCF (bioconcentration factor) value of < 2.2 indicates, that bioaccumulation is very unlikely. Since for 4,4'-sulphonyldiphenol granulometry has shown, that the amount of particles with aerodynamic diameters of 1μm or below is negligible, likewise no significant potential to deposit in the alveolar region of the lung can be anticipated.

 

Metabolism

Phenols are generally regarded as stable towards hydrolysis (Harris, 1990).

From the available in vitro mutagenicity tests in which incubations were performed in absence and presence of a metabolizing system, no metabolic activation in the human body is indicated.

Furthermore, from a comparison to known metabolic pathways of other phenolic compounds, a direct phase II conjugation with sulfate or glucuronic acid can be anticipated as the predominant metabolic reaction (e.g. US-EPA, Toxicological Review of Phenol, 2002).

 

Excretion

Due to the low Pow of 1.2, the water solubility of 1.1 g/L and the molecular weight of 250.3 g/mol excretion via the urine is expected.