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There are no in vivo data on the toxicokinetics of di-tert-nonyl-polysulfides. The following summary has therefore been prepared based onthe predicted and measured physicochemical properties of the registered substance. The data have been used in algorithms which are the basis of many physiologically based pharmacokinetic and toxicokinetic (PBTK) prediction models. Although these algorithms provide quantitative outputs, for the purposes of this summary only qualitative statements or predictions will be made because of the remaining uncertainties that are characteristic of prediction models.

The main input variable for the majority of the algorithms is the log Kow. By using this and, where appropriate, other known or predicted physicochemical properties of di-tert-nonyl-polysulfides, reasonable predictions or statements may be made about its potential absorption, distribution, metabolism and excretion (ADME) properties.

For di-tert-nonyl-polysulfides, human exposure can occur via the inhalation or dermal routes.

Absorption

Oral

Significant direct oral exposure is not expected for this substance. However, oral exposure to humans via the environment may be relevant.

When oral exposure takes place, it can be assumed that, except for the most extreme of insoluble substances, uptake through intestinal walls into the blood takes place. Uptake from intestines can be assumed to be possible for all substances that have appreciable solubility in water or lipid. Other mechanisms by which substances can be absorbed in the gastrointestinal tract include the passage of small water-soluble molecules (molecular weight up to around 200) through aqueous pores or carriage of such molecules across membranes with the bulk passage of water (Renwick, 1993).

Di-tert-nonyl-polysulfides has low solubility in water (measured water solubility <0.154 mg/l at 20°C) and has an average molecular weight of 408 g/mol, which is above the favourable range. However, should oral exposure occur, systemic exposure could take place.

Moderately high intestinal absorption rates (82% absorbed) are predicted using the pkCSM method (Pires et al, 2015).

Some systemic effects were reported in the available acute oral toxicity study demonstrating that systemic absorption can occur following oral exposure.

Dermal

The fat solubility and therefore potential dermal penetration of a substance can be estimated by using the water solubility and log Kow values. Substances with log Kow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high. Di-tert-nonyl-polysulfides has low solubility in water and has a predicted log Kow of 9 (read-across measured >5.2). Absorption of di-tert-nonyl-polysulfides across the skin is not considered to be favourable. Therefore, dermal absorption is unlikely to occur, since the substance is not sufficiently soluble in water to partition from the stratum corneum into the epidermis.

Low skin permeability (log Kp = -2.6) is also predicted using the pkCSM method (Pireset al, 2015).

There are no dermal data for the registered substance.

Inhalation

There is a QSPR to estimate the blood:air partition coefficient for human subjects as published by Meulenberg and Vijverberg (2000). The resulting algorithm uses the dimensionless Henry coefficient and the octanol:air partition coefficient (Koct:air) as independent variables.

Di-tert-nonyl-polysulfides has low solubility in water (measured water solubility <0.154 mg/l at 20°C) and also has low volatility (vapour pressure 3E-4 Pa at 25°C). This results in a moderate blood:air partition coefficient (around 3:1). Therefore, uptake into the systemic circulation from the lungs is expected. However, the low water solubility of di-tert-nonyl-polysulfides suggests that it is unlikely to be dissolved in the mucous of the respiratory tract lining, so passive absorption from the mucous is unlikely.

Some systemic effects were reported in the available acute inhalation toxicity study demonstrating that systemic absorption can occur following inhalation exposure.

Distribution

For blood:tissue partitioning a QPSR algorithm has been developed by DeJongh et al. (1997) in which the distribution of compounds between blood and human body tissues as a function of water and lipid content of tissues and the n-octanol:water partition coefficient (Kow) is described. Using this algorithm fordi-tert-nonyl-polysulfidespredicts that it will distribute approximately equal into liver, muscle, brain and kidney and to a higher degree to fat.

Table 1: Tissue:blood partition coefficients

 

Log Kow

Kow

Liver

Muscle

Fat

Brain

Kidney

Di-tert-nonyl-polysulfides

9

1E9

8.9

5.5

114

21

8.4

Distribution parameters were also predicted using the pkCSM method (Pireset al, 2015). The results are shown in the Table below.

Table 2: Distribution parameters

Di-tert-nonyl-polysulfides

Result

Comment

VDss (Human)

0.66 (log L/kg)

The steady state volume of distribution (VDss) is the theoretical volume that the total dose would need to be uniformly distributed to give the same concentration as in blood plasma.

Low = log VDss <-0.15

High = log VDss >0.45

Fraction unbound (human)

0

Fraction bound to serum proteins.

BBB permeability

0.789 (log BB)

Measures the ability of the substance to cross the blood-brain barrier.

LogBB >0.3 indicates a substance that readily crosses the blood-brain barrier; logBB <-1 indicates a substance that is poorly distributed to the brain.

CNS permeability

-2.104 (log PS)

The blood-brain permeability-surface area product (logPS) is a more direct measurement of blood brain permability.

logPS > -2 indicates substances that penetrate the Central Nervous System (CNS); log PS<-3 indicates substances unable to penetrate the CNS.

Metabolism

From information on the metabolism of other aliphatic thiols and sulfides, it is proposed that the TNPS is oxidatively metabolised in mammals via the following pathways to polar metabolites that are excreted:

1.     Thiol exchange reactions that generate a mixture of the secondary and tertiary thiols (from secondary and tertiary components of the polysulfide, respectively) (Metabolite 1). The sulfur atoms in the polysulfide are incorporated in the metabolic pool, in such compounds as glutathione, cysteine and methionine. In the case of polysulfides where n is an odd number, hydrogen sulfide (H2S) may also be produced. Hydrogen sulfide is a normal human metabolite and acts as a signalling molecule. The  levels of hydrogen sulfide are strictly controlled metabolically, so this potential metabolite is not considered further (Giuffrè, A., & Vicente, J. B., 2018).

2.     These thiols then react further according to one of the following reactions:

a.      Formation of the -S-glucuronyl conjugate from both secondary and tertiary thiols (Metabolite 2).

b.     Reaction of reduced glutathione with secondary and tertiary TNPS thiols to form glutathione conjugates (Metabolite 3).

c.      Direct oxidation of secondary and tertiary thiols to their corresponding sulfonic acids (Metabolite 4).

d.     Methylation of TNPS secondary and tertiary thiols by SAM followed by oxidation to the corresponding sulfoxides (Metabolite 5)

Metabolites 2-5 are highly polar, and it is predicted they will be excreted in the urine.

Further details and a diagram of the proposed pathways are given in the attached document.

Excretion

A determinant of the extent of urinary excretion is the soluble fraction in blood. QPSRs as developed by De Jongh et al. (1997) using log Kow as an input parameter, calculate the solubility in blood based on lipid fractions in the blood assuming that human blood contains 0.7% lipids.

Using this algorithm, the soluble fraction of di-tert-nonyl-polysulfides in blood is <1% and the substance is therefore unlikely to be eliminated via the kidneys in urine.

However, metabolism to more polar metabolites that are more effectively eliminated in urine is expected.

 

References

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Giuffrè, A., & Vicente, J. B. (2018). Hydrogen sulfide biochemistry and interplay with other gaseous mediators in mammalian physiology. Oxidative medicine and cellular longevity, 2018.

Illing, H.P.A., Dutton, G.J., (1973_. Some properties of the uridine diphosphate glucuronyltransferase activity synthesizing thio-β-d-glucuronides. Biochem. J3:139-147.

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Karthikeyan, R., Hutchinson, S.L.L. and Erickson, L.E., (2012) Biodegradation of tertiary butyl mercaptan in water. J. Bioremed. Biodegrad. 3(6)

Meulenberg, C.J. and H.P. Vijverberg, Empirical relations predicting human and rat tissue:air partition coefficients of volatile organic compounds. Toxicol Appl Pharmacol, 2000. 165(3): p. 206-16.

Pires D.E.V, Blundell T.L. and Ascher D.B (2015). pkCSM: predicting small-molecule pharmacokinetic properties using graph-based signatures, Journal of Medicinal Chemistry, 58 (0), p. 4066-4072.

Renwick A. G. (1993) Data-derived safety factors for the evaluation of food additives and environmental contaminants.Fd. Addit. Contam.10: 275-305.