1,3-bis(2,4,4-trimethylpentan-2-yl)trisulfane

Endpoint summary

Description of key information

Toxicokinetic Assessment

Absorption
Oral route
Treatment-related changes in the liver and kidney of rats receiving a daily oral dose of DAILUBE IS-30 indicates that the substance was absorbed systemically. The molecular weight of the test item will allow passive diffusion across biological membranes within the gastro- intestinal tract but this passive diffusion will be limited by the low water solubility of the test item. The high log Octanol:Water partition coefficient suggests that the test item can cross biological membranes via a selective uptake process. The limitations of absorption can explain the lack of toxicity observed in a single high dose acute oral toxicity study or may reflect lack of inherent toxicity associated with the test item

Dermal route
A single dose acute dermal toxicity study failed to demonstrate systemic effects in rats. The molecular weight and potential lipid solubility of the test item does not preclude the absorption via the dermis but either the limitations of absorption or the lack of systemic toxicity may suggest that the test material exposure via dermal absorption is likely to have negligible impact upon animals.

Inhalation route
The test item is a liquid with a relatively low vapour pressure value which suggests that inhalation of volatile components of the test item is not likely to occur. The physical characteristics of the test item suggest that there will be no inhalation of particles of the test item. Absorption across the respiratory membranes is likely to be limited by the high partition coefficient and low water solubility.

Distribution

The results of repeated dose toxicity testing indicate that some systemic distribution of the test item does take place. As the circulatory media are essentially a water based component, the limitations of distribution due to the limited water solubility of the test item will be a factor in the rate of systemic distribution. The lack of sensitization response in mice using the local Lymph Node Assay suggests that the test item is unlikely to bind to circulatory proteins in blood. The high log Octanol:Water partition coefficient value suggests that the test item has the capacity to bind to body fat. Accumulation of test item in body fat is therefore a potential event.

Metabolism

The results of histopathological evaluation of livers of rats from the repeated dose/reproduction and developmental toxicity screening assay shows evidence of hepatocyte enlargement in rats. The observation of an increase in endoplasmic reticulum in the livers of treated rats confirms the belief that induction of hepatic metabolising systems has occurred in response to exposure to the test item. It can be expected that excretion of non-water soluble xenobiotics such as the test item will be facilitated by metabolism (both phase I and II ) in the liver. The hepatic induction is seen as an adaptive change to prolonged test item exposure. The lack of genotoxicity in vitro (Mutagenesis in bacteria and mammalian cells and clastogenicity in mammalian cells) suggest that any metabolism via the S9 metabolising system does not result in an alteration of effects on these systems

Excretion

The histopathological observations from the repeated dose/reproduction toxicity assay showed evidence of renal changes associated with accumulation of α2µ globulin. It may be possible to suggest that the test item is being excreted via the kidney following rendering of the test item more soluble following hepatic metabolism. The renal effect is primarily a rodent phenomenon and is consider an adaptive response. This may therefore be of no relevance for human exposure. It does however indicate the most likely route of excretion of the test item. Any unabsorbed test material, following oral administration will be excreted via faeces.

Conclusion

The results of the rodent toxicity assays demonstrate evidence of test item absorption, distribution, metabolism and excretion. The rates of these processes are limited by the physicochemical characteristics of the test item.