1,3,4-Thiadiazolidine-2,5-dithione, reaction products with tert-dodecanethiol and hydrogen peroxide

Endpoint summary

Description of key information

The substance is expected to be absorbed to a limited extent after oral exposure, based on its rather high molecular weight (> 500 g/mol), its low water solubility and its high LogPow. Concerning the absorption after exposure via inhalation, as the chemical is considered to have a fairly low vapour pressure, is highly lipophilic, has a high LogPow, and has a rather high molecular weight, it is clear, that the substance is poorly available for inhalation and will not be absorbed significantly. The substance is also not expected to be absorbed following dermal exposure into the epidermis, due to its low water solubility and its fairly high molecular weight. Concerning its distribution throughout the body, the target substance is not expected to be distributed extensively due to the low absorption. If absorbed, it is likely to distribute into the both intravasal and intracellular compartments.
The substance does indicate a significant potential for accumulation based on the high logPow (> 8; logPow of 9.4 was determined on the read-across substance '1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol'), this, however, is limited as the absorption is expected to be low via all routes of exposure. Moreover, metabolism of the substance is expected to influence this initial prediction. The substance is expected to hydrolyse under neutral conditions (i.e. small intestines) and be extensively metabolised by cytochrome P450 enzymes, by omega- and beta-oxidation, via S-oxidation, metabolic reduction, desulfonation and possibly deamination and N-acetylation and to be eliminated mainly via the urine.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

General

The toxicokinetic profile of the target substance '1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol' was not determined by actual absorption, distribution, metabolism or excretion measurements. Rather, the physico-chemical properties of this substance were integrated with the available toxicological data to create a prediction of the toxicokinetic behavior of the target substance.

 

Toxicological profile of '1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol'

The target substance is not acutely toxic via all exposure routes. An oral LD50 > 5000 mg/kg bw, dermal LD50 > 2000 mg/kg bw and an inhalation LC50 > 2750 mg/m³ (4-hour) were established in animal studies with rats (Mason, 1998; Reckers, 1981; Findlay, 1981). The substance is not irritating to skin and eyes (Märtins, 1988) and not sensitising in guinea pigs (Grunert, 1993). The nearest analogue is not mutagenic in bacterial strains (Timm, 1989), and in mammalian cells (Mouse Lymphoma Assay conducted with cell line L5178Y) (Riach, 2013). No chromosome aberrations were detected in Chinese Hamster V79 Cells (Heidemann, 1989). Repeated oral exposures (28-day study) to the read-across substance '1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol' (CAS# 91648-65-6) revealed a NOAEL of 200 mg/kg bw (discounting all non-adverse effects at this dose level as well as kidney effects in male rats which are species-specific and are not relevant to humans, Ullmann, 1989). Similar NOAEL (250 mg/kg bw) was established for systemic effects in the Oral (gavage) reproduction/developmental toxicity screening test in the rat conducted with the read-across substance (OECD 421, Harlan, 2013). The read-across substance was not toxic to reproduction (NOAEL for reproductive performance and for neonatal toxicity is 1000 mg/kg bw).

 

Toxicokinetic analysis of 1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol

The substance is a viscous, amber coloured (clear) liquid (MW of 551 g/mol) at 20°C.The substance is insoluble in water (< 0.1 mg/L) and has LogPow of > 8 (logPow of > 9.4, determined on the short-chain homologue ‘1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol'). The substance has a low vapour pressure of 0.0021 Pa (read-across from the short-chain homologue ‘1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol’) and melting point at -4°C under atmospheric conditions. It is expected to undergo hydrolysis at pH 7 but not at pH 4 or 9.

 

Absorption

Oral absorption is not favoured for large molecules with MW > 500 g/mol (TGD, Part I, Appendix IV, 2003) which are insoluble in water. The absorption of such highly lipophilic substances may be limited by their inability to dissolve into gastrointestinal fluids. Based on the molecular weight of 551 g/mol, the low water solubility and the high logPow value, the target substance is expected not to be readily absorbed via the gastrointestinal (GI) tract by passive diffusion. This thesis is supported by the fact that the substance is practically non-toxic via oral route in the acute oral toxicity study (Mason, 1998). By repeated administration via oral route, the read-across substance produced clinical signs and findings at necropsy (hyaline droplets in kidneys). These findings point to absorption of a certain amount of the chemical into systemic circulation. Based on the physico-chemical properties which are not in the range suggestive of absorption from the gastro-intestinal tract as well as on the results of the repeated dose toxicity studies, 50% oral absorption is considered appropriate for the purposes of risk assessment (derivation of DNELs).

The target substance has estimated vapour pressure of 0.0021Pa (read-across from short-chain homologue ‘1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol’); this value points to low volatility potential. Substances with low volatilty have a vapour pressure of less than 0.5 kPa (or a boiling point above 150°C) (ECHA Guidance R7c). Boiling point of the target substance is 237°C. Based on the low vapour pressure of the target chemical, exposure by inhalation is not relevant for this substance. It is not likely, that considerable amounts of the substance reach the lung and when this occurs, the substance is not expected to be absorbed directly across the respiratory tract epithelium or through aqueous pores due to the logPow of 8.0. It was confirmed in the acute toxicity study by inhalation conducted with the read-across substance. No deaths occurred in rats at vapour concentration of 2.75 mg/L (Findlay, 1981). The effects observed in this study, were rather slightly local effects: nasal discharge, red encrustation around nose and eyes, and salivation. Based on these data, absorption by inhalation is considered not be higher than the absorption by oral route but due to the absence of substance specific information on absorption, 100% is considered for absorption by inhalation (worst case according to the ECETOC Report No 110).

Similarly, based on the physico-chemical properties, the substance '1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol' is not likely to penetrate the skin as the substance is too large (MW > 500) and insoluble in water (water solubility is < 0.1 mg/L). The substance is however sufficiently lipophilic to be taken up into the stratum corneum (logPow of > 8.0) but it will not partition from the stratum corneum into the epidermis since it is not sufficiently soluble in water. Absorption through the skin is anticipated to be low if water solubility is below 1 mg/L. (Table 3, TGD, Part I, Appendix IV, 2003). In addition, the molecular weight of 551 g/mol indicates a low potential to penetrate the skin as well. This is supported by the findings of the acute dermal toxicity study where LD50 of 2000 mg/kg bw for both sexes was established (Reckers, 1981). According to TGD, Part I (2003), 10% of dermal absorption is considered for the target substance.

 

Distribution and accumulative potential

Due to the low absorption rates via all exposure routes, a significant amount of the substance of interest is not expected to be available for distribution. As the cell membranes require a substance to be soluble in both water and lipids to be taken up, the substance is not expected to reach the inner cell compartment due to its rather high molecular weight of 551, its LogPow of > 8.0 and the low solubility in water (< 0.1 mg/L). The substance is not expected to distribute into the intravascular compartment. The substance is expected bind to proteins the fact that will hinder distribution throughout the body. As it is known that “substances with high LogPow values have long biological half-lives” (TGD, Part I, Appendix IV, 2003), a certain risk for accumulation in adipose tissues is associated with the substance. Therefore a low bioaccumulation potential was considered.

 

Metabolism

The target substance '1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol' is expected to undergo hydrolysis in body compartments where pH is in the range 5-8. The primary products of hydrolytic cleavage by S-oxidation are thioester derivatives which can be further cleaved by Phase I drugs metabolising enzyme. The possible reactions are omega- and beta-oxidation, reduction, desulfonation and possibly deamination and N-acetylation.

Excretion

Excretion via the urine is a major pathway for the oxidised and/or hydroxylated derivatives of the target substance. Metabolites which re-enter the system are expected to occur in a lesser extent. The parent substance can be excreted via the faeces.