tert-dodecanethiol

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

dermal absorption, other

Remarks:

Mathematical simulation

Type of information:

calculation (if not (Q)SAR)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Guideline:

other: REACH Guidance on QSARs R.6

Principles of method if other than guideline:

IH SkinPerm mathematical tool for estimating dermal absorption

Time point:

8 h

Dose:

1000 mg/h (deposition)

Parameter:

percentage

Absorption:

0 %

Reference 2

Endpoint:

basic toxicokinetics, other

Remarks:

G.I. human passive absorption

Type of information:

calculation (if not (Q)SAR)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

absorption

Guideline:

other: REACH Guidance on QSARs R.6

Principles of method if other than guideline:

Model to predict either high or low fraction absorbed for an orally administered, passively transported substance on the basis of a new absorption parameter. The model includes only two inputs: the octanol-water partition coefficient (Kow) and the dimensionless oversaturation number (OLumen). The latter is the ratio of the concentration of drug delivered to the gastro-intestinal (GI) fluid to the solubility of the compound in that environment.

Specific details on test material used for the study:

SMILES (used for QSAR prediction): C(C)(C)(S)C(C)(C)C(C)(C)C(C)C

Species:

other: Human

Route of administration:

oral: unspecified

Type:

absorption

Results:

Absorption from gastrointestinal tract for 1 mg dose: 100%

Type:

absorption

Results:

Absorption from gastrointestinal tract for 1000 mg dose: 90%

Description of key information

No data on toxicokinetics, metabolism and distribution are available for tert-dodecanethiol (TDM). Based on its physicochemical properties, TDM is expected to be well absorbed by the respiratory and gastro-intestinal tracts; Limited absorption is expected through the skin.

The assessment of the toxicokinetics of TDM is based on the available toxicological data and the physicochemical properties of TDM as suggested by the REACH Guidance Chapter R.7c:

Molecular weight: 202.4 g/mole 

Vapeur pressure: 20 Pa @ 25°C

Water solubility: 3.93 µg/L at 20°C 

Partition coefficient log Kow = 7.43

 

ABSORPTION

Oral route

TDM is a highly lipophilic substances (log Kow 7.43 and low water solubility), its absorption may be limited by its inability to dissolve into GI fluids and hence make contact with the mucosal surface. However, as any highly lipophilic and poorly soluble in water compounds, TDM may be taken up by micellular solubilisation.

Using a model to predict either high or low fraction absorbed for an orally administered, passively transported substance, the rates of absorption were 100 and 90% for a dose of 1 and 1000 mg, respectively.

100% of oral absorption is taken into account for risk assessment.

 

Inhalation route

TDM is a substance with a low volatility, its vapour pressure is 20 Pa at 25°C and its boiling point is 238°C at 1013 hPa. As any highly lipophilic and poorly soluble in water compounds, TDM may be taken up by micellular solubilisation. This assumption of inhalation absorption is supported by the toxic effects observed in a repeated inhalation toxicity studied in rats, dogs and mice with TDM (Triel, 2017; Ulrich et al., 1985).

100% of inhalation absorption is taken into account for risk assessment.

 

Dermal absorption

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. Above a logP of 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.

The rate of absorption was estimated using the IH SkinPerm model using a Kp derived from the EPI Dermwin model. For a skin deposition of 1000 mg/h for 8 h, TDM is virtually not absorbed.

Therefore, according to the REACH Guidance, a default value of 10% skin absorption will be used for TDM in risk assessment.

 

DISTRIBUTION and METABOLISM

According to the REACH Guidance R.7c, as a relatively small molecule a wide distribution of TDM is expected.

It is generally recognized (WHO document at http://www.inchem.org/documents/jecfa/jecmono/v44jec09.htm) that thiols are metabolized via several different pathways in vertebrates.

 

Simple aliphatic thiols undergo S-methylation in mammals to produce the corresponding methyl thioether or sulfide. Methylation is catalysed by thiopurine methyltransferase in the cytoplasm and thiol methyltransferase in microsomes, and both reactions requireS-adenosyl-1-methionine as a methyl group donor. Thiopurine methyltransferase is present in human liver, kidney, and erythrocytes; preferential substrates for this enzyme include aromatic and heterocyclic thiols. S-Methylation of aliphatic thiols is catalysed by microsomal thiol methyltransferase, and the resulting methyl thioether (sulfide) metabolite would undergo S-oxidation to give the methyl sulfoxide and methyl sulfone analogues as urinary products.

 

Thiols may react with glutathione and other endogenous thiol substances to form mixed disulfides. Both microsomal and cytoplasmic thioltransferases have been reported to catalyse the formation of mixed disulfides. The resulting mixed disulfides can undergo reduction back to thiols, oxidative desulfuration, or oxidation to a sulfonic acid via the intermediate thiosulfinate and sulfinic acids. The principal form in the circulation would probably be a mixed disulfide formed with albumin.

 

Thiols may be oxidized to form sulfenic acids (RSOH), which are unstable and readily undergo further oxidation to sulfinic (RSO2H) and sulfonic (RSO3H) acids or combine with nucleophiles. The sulfonic acid group is a highly polar centre and makes molecules highly soluble in water. In general, sulfonic acids are stable to metabolism.

 

Each of these cellular pathways would provide supporting evidence of the likely metabolism of TDM.

 

ELIMINATION

 

According to the REACH Guidance R. 7c, it is generally the case that substances with high log P values have long biological half-lives. On this basis, daily exposure to a substance with a log P value of around 4 or higher could result in a build up of that substance within the body. However, the metabolism of TDM leads to more hydrophilic substances that are easily excreted in the urines. Therefore, no bioaccumulation is expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100