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EC number: 293-927-7
CAS number: 91648-65-6
The substance is expected to be absorbed to a limited extent after oral exposure, based on its rather high molecular weight (466.86 g/mol, which is at the upper limit favourable for absorption), 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 (9.4), 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.
toxicokinetic profile of 1,3,4-Thiadiazolidine-2,5-dithione, reaction
products with hydrogen peroxide and tert-nonanethiol 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.
reaction products with hydrogen peroxide and tert-nonanethiol
target substance is not acutely toxic via all exposure routes. An oral
LD50 > 10,000 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
(Reckers, 1981a,b; Findlay, 1981). The substance is not irritating to
skin and eyes (Reckers, 1981c, Reckers, 1982) and not sensitizing in
guinea pigs (Rodabaugh, 2006; Smedley, 2003). It 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) 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 (OECD 421,
Harlan Laboratories, 2013). The substance was not toxic to reproduction
(NOAEL for reproductive performance and for neonatal toxicity is 1000
analysis of 1,3,4-Thiadiazolidine-2,5-dithione, reaction products with
hydrogen peroxide and tert-nonanethiol
substance is a viscous, liquid with a pungent odour (MW of 466.84 g/mol)
substance is insoluble in water (< 1.0 x 10-4 g/L) and the LogPow was
determined as > 9.4. It has a low vapour pressure of 0.0021 Pa and has
its pour point at -3 +/- 3°C under atmospheric conditions. It is
expected to undergo hydrolysis at pH 7 but not at pH 4 or 9.
absorption is not favoured for large insoluble in water molecules with
MW >500 (TGD, Part I, Appendix IV, 2003). The absorption of such highly
lipophilic substances may be limited by their inability to dissolve into
gastrointestinal fluids. Based on the molecular weight of 466.84 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 (Reckers, 1981a). By repeated administration via oral
route, the target substance produced clinical signs and findings at
necropsy (hyaline droplets in kidneys) which 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).
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 9.4. It was confirmed in the acute toxicity study by inhalation. 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
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).
based on the physico-chemical properties of the target substance, the
substance is not likely to penetrate the skin as the substance is too
large (MW of near 500) and insoluble in water (water solubility is under
1.0 x 10-4g/L). The substance is however sufficiently
lipophilic to be taken up into the stratum corneum (logPow of 9.4 ) 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
466.84 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,
1981b). According to TGD, Part I (2003), 10% of dermal absorption is
considered for the target substance.
and accumulative potential
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 466.84, its LogPow of 9.4 and the low solubility in water (1.0 x 10-4g/L
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.
target substance 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.
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.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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