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

Dermal absorption

Administrative data

Endpoint:

dermal absorption

Type of information:

other: Expert statement

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

An extensive Assessment of the toxicological behaviour of 1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol was performed, taking into account the chemical structure, the available physico-chemical-data and the available (eco-)toxicological data.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Test guideline

Qualifier:

no guideline required

Test material

Test material information

Constituent 1

Reference substance name:

5-[(2,2-dimethyldecyl)disulfanyl]-1,3,4-thiadiazole-2-thiol; bis[(2,2-dimethyldecyl)disulfanyl]-1,3,4-thiadiazole

EC Number:

939-692-2

Cas Number:

1474044-73-9

Molecular formula:

not applicable (UVCB substance)

IUPAC Name:

5-[(2,2-dimethyldecyl)disulfanyl]-1,3,4-thiadiazole-2-thiol; bis[(2,2-dimethyldecyl)disulfanyl]-1,3,4-thiadiazole

Radiolabelling:

other: not applicable in this expert statement

Test animals

Details on test animals or test system and environmental conditions:

not applicable in this expert statement

Results and discussion

Percutaneous absorption

Parameter:

percentage

Absorption:

10 %

Remarks on result:

other: Due to the molecular weight of 551, high logPow (8; 9.4 for the read-across substance) and the results for acute dermal toxicity in animals, the use of a factor of 10 % for the estimation of dermal uptake is justified

Any other information on results incl. tables

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-dodecanethiol, the molecular weight is 551, which indicates already a low potential to penetrate the skin. This is accompanied by a very low hydrophilicity of the substance (LogPow of 8; 9.4 for the read-across 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 of 1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol,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-dodecanethiol 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-dodecanethiol is justified(Schuhmacher –Wolz et al.,2003; TGD, Part I, 2003).

Applicant's summary and conclusion

Conclusions:

An extensive Toxicological Statement for 1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol was performed (expert statement), taking into account the chemical structure, the available physico-chemical-data and the available (eco-)toxicological data.

Executive summary:

In order to assess the toxicological behaviour of 1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol, 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 (551 g/mol, which is above 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 (8; logPow of 9.4 was identified for the read-across substance), 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.