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EC number: 293-927-7 | CAS number: 91648-65-6
Absorption following dermal exposure
In order to cross the skin, a compound must first penetrate into the stratum corneum and may subsequently reach the epidermis, the dermis and the vascular network. The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the epidermis is most resistant to penetration by highly lipophilic compounds. Substances with a molecular weight below 100 are favourable for penetration of the skin and substances above 500 are normally not able to penetrate. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore if the water solubility is below 1 mg/L, dermal uptake is likely to be low. Additionally, LogPow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal; TGD, Part I, Appendix IV). Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow too. Vapours of substances with vapour pressures below 100 Pa are likely to be well absorbed and the amount absorbed dermally is most likely more than 10% of the amount that would be absorbed by inhalation (TGD, Part I, Appendix IV, 2003). If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. During the whole absorption process into the skin, the compound can be subject to biotransformation.
In case of 1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol, the molecular weight is around 500, which indicates already a low potential to penetrate the skin. This is accompanied by a very low hydrophilicity of the substance and even though the stratum corneum is open for lipophilic substances, the epidermis is very resistant against penetration by highly lipophilic substances. In addition, the amount of1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol,which is absorbed following dermal exposure into the stratum corneum is unlikely to be transferred into the epidermis. 1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol is not irritating to skin and eyes, and therefore this does not enhance dermal absorption. The vapour pressure of the substance is very low (0.0021 Pa) and therefore it will not partition into the air. Thus, no skin exposure is expected by airborne concentrations of the target substance.
In support of this hypothesis (the very low dermal absorption), the systemic toxicity via the skin is low (acute dermal toxicity, LD50 value of > 2000).
In conclusion, the evaluation of all the available indicators and the results of toxicity studies allow the allocation of the chemical in question into the group of chemicals with a low dermal absorption. In detail, due to it’s molecular weight and the results for acute toxicity, the use of a factor of 10 % for the estimation of dermal uptake for 1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol is justified(Schuhmacher –Wolz et al.,2003; TGD, Part I, 2003).
In order to assess the toxicological behaviour of 1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol,the available physico-chemical and toxicological data have been evaluated. 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 substanceis 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 lowvia 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 metabolisedby cytochrome P450 enzymes, by omega- and beta-oxidation, via S-oxidation, metabolic reduction, desulfonation and possibly deamination andN-acetylation andto be eliminated mainly via the urine.
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