Bis(4-chlorophenyl) sulphone

Endpoint summary

Additional information

The toxicokinetic behaviour of DCDPS was studied in rats after single i.v. and oral as well as after repeated oral administration of uniformly¹⁴C labelled DCDPS (Mathews et al., 1996). The distribution of unlabelled DCDPS during a 4-week feeding was studied by Poon et al. (1999). There are no experimental data available on DCDPS toxikokinetics following dermal or inhalation exposure.

Absorption

Absorption of DCDPS from the gastrointestinal tract was estimated by comparative studies after administration of 10 mg/kg bw doses by oral gavage or by intravenous injection. The data showed that oral absorption occurred rapidly and was nearly complete. With increasing doses oral absorption was linear up to at least 100 mg/kg bw. Even at the high dose of 1000 mg/kg bw oral bioavailability remained high (>50 %) (Mathews et al., 1996).

Based on the MW of 287.2 and the log Pow of 3.9 in combination with the low water solubility of 0.86 mg/L a moderate dermal absorption of DCDPS is assumed. This assumption is supported by the dermal permeation coefficient (Kp) of 0.015 cm/h, which was determined in silico with DERMWIN v2.00.

DCDPS is a crystalline solid with a negligible vapour pressure of 5.1x 10^-6Pa at 20 °C and a mean particle size of 240 µm. Less than 10 % of the particles are below the size of 100 µm and no particles are below 10 µm. Therefore, the small fraction of the substance which can be inhaled will be deposited in the bronchiotracheal area and subsequently transferred to the digestive system via the mucociliary cleansing mechanism. Practically no substance will be available for absorption in the gas exchange region.

At process temperatures above the melting point vapours can arise which might lead to the formation of particles within the respirable size. However, bioavailability in the gas exchange region might be hampered by the low water solubility of the substance and thus, a minor dissolution in the bronchoalveolar liquid.

Distribution

DCDPS distributed rapidly out of blood into tissues. The amount of radioactivity in the tissues followed the order adipose tissue >> skin > muscle >> liver > kidney > blood, lung, spleen, brain (Poon et al., 1999, Mathews et al., 1996). Increasing concentrations in adipose were observed up to 24 hours, followed by elimination with a terminal half-live of ~12 hours.Virtually all radioactivity in adipose tissue was assigned to unmetabolised DCDPS. In all other tissues at least 90 % of the radioactivity deposited was parent substance, except in livers of animals dosed at 1000 mg/kg bw, where it was ~80 %(Mathews et al., 1996).Distribution was unaffected by dose or route of administration. Tissue/blood ratios were comparable after single i.v. and oral administration (ratio for adipose tissue ~100, for lean tissues such as liver and kidney ~3-7).

Repeated oral administration of 10 mg/kg bw/d resulted in concomitant decrease in the percentage of dose retained in tissues with increasing treatment time and when compared with single-dose data (85.5 %, 41.1 %, 28.3 %, 22.8 % or 10.1 % of dose present in tissues 72 hours after single, 7-days, 2-wks, 3-wks or 5 wks of repeated administration, respectively). The contribution of deposition in adipose on these percentages was 57 % and constantly 67 % after single and repeated oral treatment, respectively.

Repeated oral administration over 2 to 5 weeks showed that radiochemical content in adipose tissue peaked at ~3 weeks, whereas in kidney, liver and skin concentrations were near maximum after ~2 weeks and remained relatively constant thereafter. Apparent steady-state was reached after ~2-3 weeks of repeated dosing (Mathews et al., 1996). In the repeated oral dose study by Poon et al. (1999) the levels of DCDPS in adipose and liver tissue remained unchanged from week 1 to week 4, whereas an increase of the DCDPS level with time was seen in the kidneys.

Metabolism

The main metabolites identified in urine and faeces were the oxidation product mono-hydroxy-DCDPS (hydroxy-moiety in the meta-position to the sulfone) and its respective glucuronide. They aroused most likely from phase I and II metabolism in the liver. Furthermore, minor metabolites were found (up to 5 components), but not further characterised. The presence of the aglykone in faeces but not in bile leads to the assumption that the glucuronide was hydrolysed in the gastrointestinal tract. Significant first-pass metabolism can be excluded because within 24 hours after administration the amount of radioactivity excreted (containing primarily metabolites) was small (~4.5 % of total dose) and did not differ between oral and i.v. administration. Furthermore, DCDPS is primarily (> 90 % up to 100 %) deposited in tissues as parent compound, indicating that first-pass metabolism followed by deposition of metabolites in tissues is also not relevant.

The percentage of the applied dose excreted as metabolites increased with increasing dose and also from single to repeated dosing schedules. This demonstrates that DCDPS induced its own metabolism and is in line with the induction of cytochrome P450 isoenzymes, UDP-glucuronosyltransferase and gluthathione S-transferase reported by Poon et al. (1999) after repeated oral dosing. Furthermore, PBPKmodelling of the toxicokinetics supports the view that DCDPS induces enzymes involved in its metabolism (Parham et al., 2003).

Excretion

Excretion of DCDPS derived radioactivity was independent from the route of application. Excretion of DCDPS in urine and faeces was dependent on metabolism to more polar compounds (mainly mono-hydroxy-DCDPS and its respective glucuronide), and relatively little parent compound was excreted before metabolism. After a single i.v. dose excretion of radioactivity was slow but nearly linear and accounted for 28 % of the total dose in 7 days. The terminal half-live of DCDPS in adipose tissue was ~ 12 days. Elimination in faeces exceeded that in urine by 1.5- to 3- fold after single i.v., single oral or repeated oral administration (72 hours p.a.). Three days p.a. the amount of total dose excreted was two fold higher after 7-day repeated oral administration than after single oral administration and also increased with dose (20 and 27 % at 10 and 100 mg/kg bw, respectively, in the single dose study versus 49 and 54 % at 10 and 100 mg/kg bw, respectively, in the repeat dose study). This correlates with the observed induction of metabolism with time and dose.