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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

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Administrative data

Link to relevant study record(s)

Description of key information

Absorption

No studies on absorption and excretion of propane-1-thiol and propane-2-thiol are available. However, predictions based on physicochemical properties and evidence from acute toxicity studies suggest that the substances are absorbed following exposure. Given the high volatility, high water solubility and low log Kowof substances, most excretion is expected to be via the urine or in exhaled breath.

Oral route

Propane-1-thiol and propane-2-thiol have a molecular weight of 76.15, and molecular weights below 500 are favourable for oral absorption. The substances have a moderate water solubility (1.9/3.7 g/L) and a moderate logP (1.68/1.81) which is also favorable for absorption by passive diffusion. Mortalities and signs of systemic toxicity observed in the acute oral toxicity studies are also indicative of a significant oral absorption.

Using a model to predict either high or low fraction absorbed for an orally administered, passively transported substance, high rates of absorption from the gastrointestinal tract were predicted propane-1-thiol and propane-2-thiol (Danish QSAR database).

Absorption from the gastrointestinal tract (%)

Dose

Propane-1-thiol

107-03-9

Propane-2-thiol

75-33-2

1 mg

90

90

1000 mg

90

90

 

As well, high absorption rates were also predicted for both substances with the pkCSM method (ca. 90%) (Pires et al., 2015) and the ADMETlab platform (70-90%) (Dongsheng Cao et al., 2018).

Inhalation exposure

Based on the high vapour pressure of propane-1-thiol and propane-2-thiol, inhalation exposure is likely. With log P values of 1.81 and 1.68, respectively, propane-1-thiol and propane-2-thiol are expected to be absorbed directly across the respiratory tract epithelium by passive diffusion. The mortality and/or clinical signs observed in the acute inhalation toxicity studies give also the indication of a significant inhalation absorption.

Dermal absorption

The dermal absorption rates ofpropane-1-thiol and propane-2-thiolwere estimated with IH SkinPerm v2.04 model (AIHA, 2018). Compared toin vitrodata from OECD 428 studies, IH skinPerm allowed the estimation of the dermal absorption rate with a good confidence and a low frequency (ca. 2%) of underestimation for liquids (Arkema’s internal validation study, 2018). According to the data input, IH SkinPerm v2.04 model leads to the following results:

 

Fraction absorbed (%)*

Instantaneous deposition
(1000 mg/1000 cm²)

Deposition over time
(1mg/cm²/h)

Propane-1-thiol

107-03-9

0.55

1.08

Propane-2-thiol

75-33-2

0.36

0.59

*End time observation 8 hr

For both compounds, the skin absorption rates were similar and very low.

 

Distribution

When reaching the body,propane-1-thiol and propane-2-thiolmay be distributed into cells due to their lipophilic properties and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues.

The evaluation ofpropane-1-thiol and propane-2-thiolin the pkCSM method (Pireset al., 2015) for predicting small-molecule pharmacokinetic properties does not show any significant differences in the models related to distribution.

Model Name

Predicted Value

Propane-2-thiol

Propane-1-thiol

VDss (human)

0.033

0.062

Fraction unbound (human)

0.657

0.68

BBB permeability

0.064

0.11

CNS permeability

-2.08

-2.307

 

As well, similar parameters related to distribution were predicted forpropane-1-thiol and propane-2-thiolwith the ADMETlab platform (Dongsheng Caoet al., 2018).

Property

Propane-1-thiol

Propane-2-thiol

Meaning & Preference

PPB (Plasma Protein Binding)

44.654 %

47.832 %

Significant with drugs that are highly protein-bound and have a low therapeutic index.

VD (Volume Distribution)

0.044 L/kg

-0.156 L/kg

Optimal: 0.04-20L/kg;

Range:

<0.07L/kg: Confined to blood, Bound to plasma protein or highly hydrophilic; 0.07-0.7L/kg: Evenly distributed; >0.7L/kg: Bound to tissue components (e.g., protein, lipid),highly lipophilic.

BBB (Blood–Brain Barrier)

+++

+++

BB ratio >=0.1: BBB+; BB ratio <0.1: BBB-

These features tend to improve BBB permeation:

H-bonds (total) < 8–10; MW < 400–500; No acids.

 

Metabolism

Simple thiol flavouring agents have been assessed by the Joint FAO/WHO Expert Committee on Food Additives (JECFA, 2000). Metabolic pathways for thiols are described in detail in that document:

Simple aliphatic and aromatic thiols undergo S-methylation in mammals to produce the corresponding ethyl thioether or sulfide. Methylation is catalysed by thiopurine methyltransferase in the cytoplasm and thiol methyltransferase in microsomes, and both reactions require S-adenosyl-l- 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 cytoplasmlic 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 S-Glucuronidation of aromatic thiols has been reported, and this may be a pathway for the metabolism of aromatic thiols (thiophenols) (Nos 525 and 528-531) and simple aromatic disulfides (Nos 576 and 578; subgroup vii) after their reduction (see below). Glucuronyl transferases behave similarly towards hydroxyl and sulfydryl groups, and the two activities have the same subcellular location and optimal pH. 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 molelcules highly soluble in water. In general, sulfonic acids are stable to metabolism.

Alkyl thiols of low relative molecular mass undergo oxidative desulfuration in vivo to yield CO2and SO4=. This reaction has been shown, for example, for methanethiol (methyl mercaptan). hereas the carbon atom from thiols may be used in the biosynthesis of amino acids, the sulfur atom is not used significantly in the synthesis of sulfur-containing amino acids.

 

The metabolism of di-n-propyl disulphide (DPDS), was investigatedin vivoin the rat (Germain et al., 2008). A single dose (200 mg/kg)) was administered by gastric intubation and the time courses of DPDS and its metabolites were followed over 48 h by gas chromatography coupled with mass spectrometry in the stomach, intestine, liver, and blood. DPDS was detected in the stomach where it was transformed into n-propyl mercaptan (propane-1-thiol), whereas the liver contained only traces of DPDS and none at all in the other examined organs. The metabolites methylpropyl sulphide, methylpropyl sulphoxide (MPSO), and methylpropyl sulphone (MPSO2) were sequentially formed in the liver from n-propyl mercaptan. The route of elimination from the liver seemed to be mainly via the blood. The bile also participated in the excretory process, but only for MPSO2. The pharmacokinetic parameters were determined for all of the above compounds. Whereas the bioavailability of DPDS was very low (0.008 h mM), the areas under the curve were higher for n-propyl mercaptan, i.e. 3.44 h mM and the S-oxidized metabolites MPSO and MPSO2, i.e. 9.64 and 24.15 h mM, respectively. The half-lives for DPDS and its metabolites varied between 2.0 and 8.25 h, except for MPSO2, which had a half-life of 29.6 h. MPSO2was the most abundant and persistent of these metabolites.

Propane-1-thiol and propane-2-thiolare therefore all expected to follow similar metabolic pathways.

 

Excretion

The evaluation of propane-1-thiol and propane-2-thiol in the pkCSM (Pires et al., 2015) and ADMETlab (Dongsheng Cao et al., 2018) platforms does not show any significant differences in the parameters related to excretion.

 

pkCSM model name

Predicted Value

Propane-2-thiol

Propane-1-thiol

Total Clearance (log ml/min/kg)

0.281

0.232

Renal Organic Cation Transporter 2 (OCT2) substrate

no

no

 

ADMETlab property

Propane-1-thiol

Propane-2-thiol

Meaning & Preference

T1/2(Half Life Time)

1.483 h

1.768 h

Range: >8h: high; 3h< Cl < 8h: moderate; <3h: low

CL (Clearance Rate)

1.071 mL/min/kg

1.011 mL/min/kg

Range: >15 mL/min/kg: high; 5mL/min/kg< Cl < 15mL/min/kg: moderate; <5 mL/min/kg: low

 

 

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
90
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
100

Additional information