Di-tert-butyl trisulphide

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

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:

results derived from a (Q)SAR model, with limited documentation / justification, but validity of model and reliability of prediction considered adequate based on a generally acknowledged source

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)(C)CSSCC(C)(C)C
Molecular Formula: C10 H22 S2

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%

Reference 2

Endpoint:

basic toxicokinetics, other

Remarks:

in silico

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

See enclosed files

Objective of study:

absorption

distribution

excretion

metabolism

Qualifier:

according to guideline

Guideline:

other: REACH Guidance on QSARs R.6

Qualifier:

according to guideline

Guideline:

other: REACH Guidance on IR&CSA, Chapter R.14, Occupational exposure assessment Update to change the scope of the guidance from exposure estimation to exposure assessment

Version / remarks:

August 2016

Principles of method if other than guideline:

pkCSM uses graph-based signatures to develop predictive models of central ADME properties. pkCSM performs as well or better than current methods.

Specific details on test material used for the study:

SMILES for QSAR prediction:
C(C)(C)(C)CSSSCC(C)(C)C
C(C)(C)(C)CSSSSCC(C)(C)C
C(C)(C)(C)CSSSSSCC(C)(C)C

Type:

absorption

Results:

Intestinal absorption (human): 88.742, 86.758, 85.013 (S3, S4, S5, respectively)

Type:

distribution

Results:

VDss (human) (log L/kg): 0.287, 0.29, 0.296 (S3, S4, S5, respectively)

Type:

distribution

Results:

Fraction unbound (human) : 0.188, 0.159, 0.126 (S3, S4, S5, respectively)

Type:

distribution

Results:

BBB permeability (log BB): 0.74, 0.732, 0.721 (S3, S4, S5, respectively)

Type:

distribution

Results:

CNS permeability (log PS): -1.351, -1.424, -1.496 (S3, S4, S5, respectively)

Type:

excretion

Results:

Total Clearance (log ml/min/kg): 0.246, 0.132, 0.014 (S3, S4, S5, respectively)

Type:

excretion

Results:

Renal OCT2 substrate: no, no, no (S3, S4, S5, respectively)

		Di-tert-butyl polysulphide
		S3	S4	S5
Property	Model Name	Predicted Value			Unit
Absorption	Water solubility	-6.276	-6.688	-7.062	Numeric (log mol/L)
Absorption	Caco2 permeability	1.449	1.451	1.454	Numeric (log Papp in 10^-6cm/s)
Absorption	Intestinal absorption (human)	88.742	86.758	85.013	Numeric (% Absorbed)
Absorption	Skin Permeability	-1.03	-1.233	-1.494	Numeric (log Kp)
Absorption	P-glycoprotein substrate	No	No	No	Categorical (Yes/No)
Absorption	P-glycoprotein I inhibitor	No	No	No	Categorical (Yes/No)
Absorption	P-glycoprotein II inhibitor	No	No	No	Categorical (Yes/No)
Distribution	VDss (human)	0.287	0.29	0.296	Numeric (log L/kg)
Distribution	Fraction unbound (human)	0.188	0.159	0.126	Numeric (Fu)
Distribution	BBB permeability	0.74	0.732	0.721	Numeric (log BB)
Distribution	CNS permeability	-1.351	-1.424	-1.496	Numeric (log PS)
Metabolism	CYP2D6 substrate	No	No	No	Categorical (Yes/No)
Metabolism	CYP3A4 substrate	No	No	No	Categorical (Yes/No)
Metabolism	CYP1A2 inhibitior	No	Yes	Yes	Categorical (Yes/No)
Metabolism	CYP2C19 inhibitior	No	Yes	Yes	Categorical (Yes/No)
Metabolism	CYP2C9 inhibitior	No	No	No	Categorical (Yes/No)
Metabolism	CYP2D6 inhibitior	No	No	No	Categorical (Yes/No)
Metabolism	CYP3A4 inhibitior	No	No	No	Categorical (Yes/No)
Excretion	Total Clearance	0.246	0.132	0.014	Numeric (log ml/min/kg)
Excretion	Renal OCT2 substrate	No	No	No	Categorical (Yes/No)
Toxicity	AMES toxicity	No	No	No	Categorical (Yes/No)
Toxicity	Max. tolerated dose (human)	0.312	0.276	0.23	Numeric (log mg/kg/day)
Toxicity	hERG I inhibitor	No	No	No	Categorical (Yes/No)
Toxicity	hERG II inhibitor	No	No	No	Categorical (Yes/No)
Toxicity	Oral Rat Acute Toxicity (LD50)	2.313	2.625	2.94	Numeric (mol/kg)
Toxicity	Oral Rat Chronic Toxicity (LOAEL)	1.325	1.171	-0.104	Numeric (log mg/kg_bw/day)
Toxicity	Hepatotoxicity	No	No	No	Categorical (Yes/No)
Toxicity	Skin Sensitisation	Yes	Yes	Yes	Categorical (Yes/No)
Toxicity	T.Pyriformistoxicity	2.227	2.515	2.632	Numeric (log ug/L)
Toxicity	Minnow toxicity	-0.526	-0.787	-1.095	Numeric (log mM)

Reference 3

Endpoint:

basic toxicokinetics, other

Remarks:

in silico

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Objective of study:

metabolism

Qualifier:

according to guideline

Guideline:

other: REACH Guidance on QSARs R.6

Qualifier:

according to guideline

Guideline:

other: REACH Guidance on IR&CSA, Chapter R.14, Occupational exposure assessment Update to change the scope of the guidance from exposure estimation to exposure assessment

Version / remarks:

August 2016

Principles of method if other than guideline:

Xenosite P450 Metabolism 1.0 is a software predicting site of metabolism (SOM) of a molecule for cytP4501A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 CYP isoforms. Xenosite P450 Metabolism 1.0 computes a probability score varying between 0 and 1 (a high probability to be a SOM is characterized by a high score), which reflects both the confidence of the model that a particular atom is metabolised and the statistical likelihood that its prediction for that atom is correct, but they do not explicit model selectivity (which molecules are substrates of a given CYP enzyme).

Specific details on test material used for the study:

SMILES for QSAR prediction:
C(C)(C)(C)CSSSCC(C)(C)C
C(C)(C)(C)CSSSSCC(C)(C)C
C(C)(C)(C)CSSSSSCC(C)(C)C

Type:

metabolism

Results:

S3, S4 and S5 components of di-tert-butyl polysulphide are preferentially metabolized on the disulphide bridges.

Metabolites identified:

no

Executive summary:

The metabolism of S3, S4 and S5 components of di-tert-butyl polysulphide by cytP450 was evaluated by the Xenosite P450 Metabolism 1.0 software. XenoSite is able to predict the site of metabolism (SOM) of a molecule for cytP4501A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 CYP isoforms. Xenosite computes a probability score varying between 0 and 1 (a high probability to be a SOM is characterized by a high score), which reflects both the confidence of the model that a particular atom is metabolised and the statistical likelihood that its prediction for that atom is correct, but they do not explicit model selectivity (which molecules are substrates of a given CYP enzyme). According to the cyt P450 isoforms and the S3, S4 and S5 components of di-tert-butyl polysulphide are preferentially metabolized on the disulphide bridges.

Reference 4

Endpoint:

dermal absorption, other

Remarks:

QSAR

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Qualifier:

according to guideline

Guideline:

other: REACH Guidance on QSARs R.6

Qualifier:

according to guideline

Guideline:

other: REACH Guidance on IR&CSA, Chapter R.14, Occupational exposure assessment Update to change the scope of the guidance from exposure estimation to exposure assessment

Principles of method if other than guideline:

IH SkinPerm (v2.04) is a mathematical tool for estimating dermal absorption. The rate of mass build-up (or loss) on the skin comes from the deposition rate onto the skin minus the absorption rate into the Stratum Corneum (SC) and the amount evaporating from the skin to the air.

Species:

other: human

Type of coverage:

open

Vehicle:

unchanged (no vehicle)

Details on study design:

DATA INPUT
Molecular weight: 206.41.29 g/mol
Temperature: 20 °C
Vapour Pressure: 15.6 Pa
Water solubility: 4 mg/L
Log Kow: 5.6
Density: 999.5 mg/cm3
Melting point: -11°C

SCENARIO PARAMETERS
- Instantaneous deposition
Deposition dose*: 1000 mg
Affected skin area**: 1000 cm²
Maximum skin adherence***: 2 mg/cm²
Thickness of stagnant air****: 1 cm
Weight fraction: 1
Timing parameters
. Start deposition: 0 hr
. End time observation: 8 hr
Report parameters
. Calculation (intervals/hr): 10000
. Report (intervals/hr): 100

- Deposition over time
Affected skin area**: 1000 cm²
Maximum skin adherence***: 1 mg/cm²
Dermal deposition rate: 2 mg/cm²/hr
Thickness of stagnant air****: 1 cm
Weight fraction: 1
Timing parameters
. Start deposition: 0 hr
. Duration of deposition: 8hr
. End time observation*: 8 hr
Report parameters
. Calculation (intervals/hr): 10000
. Report (intervals/hr): 100

*Default value defined according to the internal validation study
**Estimated skin surface of two hands of an adult.
***The skin adherence field is greyed out and a default of -1 is indicated if the substance is a liquid at 25°C. Smart logic is built into IH SkinPerm; the program recognizes whether a substance is a solid or liquid at standard temperature (25°C) based on the physicochemical properties. For substances
that are solids at 25°C a maximum adherence value up to 2 mg/cm² is allowed based on studies of soil-on-skin adherence. If the deposition rate results in an increase above the input figure (0.2-2 mg/cm²), it is assumed that the surplus disappears just by removal from the skin.
*** 3 cm if clothing involved, 1 cm if bare skin involved

Time point:

8 h

Dose:

1000 mg

Parameter:

percentage

Absorption:

8.02 %

Remarks on result:

other: Instantaneous deposition

Time point:

8 h

Dose:

1 mg/cm²/h

Parameter:

percentage

Absorption:

1 %

Remarks on result:

other: Deposition over time for 8 hr

Conclusions:

The dermal absorption of di-tert-butyl polysulphide is estimated to be low (<= 10%).

Executive summary:

The dermal absorption of di-tert-butyl polysulphide leads to the following results, obtained using the SkinPerm v2.04 model according to the input data:

	Instantaneous deposition	Deposition over time End time observation 8 hr
Total deposition (mg) or deposition rate (mg/cm²/hr)	1000	1
Fraction absorbed (%)	8.02	1
Amount absorbed (mg)	80.2	80.2
Lag time stratum corneum (min)	2.94
Max. derm. abs. (mg/cm²/h)	0.00501

Description of key information

No data on toxicokinetics, metabolism and distribution are available for the registered substance.

ABSORPTION

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

Molecular weight : 206 g/mol

Vapeur pressure: 15.6 Pa @ 20°C

Water solubility: 4 mg/L at 20°C 

Partition coefficient log Kow = 5.6

Based on its physicochemical properties, the registered substance is expected to be well absorbed by the respiratory and gastro-intestinal tracts. Limited absorption is expected through the skin.

Oral route

The registered substance is a highly lipophilic substance (log Kow 5.6) with a very low water solubility, therefore 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, it may be taken up by micellular solubilisation.

According to the hydrolysis study (Mollandin, 2011), the registered substance is not expected to hydrolyse at pH relevant to the GI tract.

Using a model to predict either high or low fraction absorbed for an orally administered, passively transported substance, the rates of absorption of the registered substance were 100 and 90% for a dose of 1 and 1000 mg, respectively (Danish QSAR). Similarly, oral human absorption rates of 85-88% were predicted by the pkCSM method (Pires et al., 2015) for the main components (S3, S4 and S5 fractions) of the registered substance.

In addition, the toxicological effects observed during the repeated dose toxicity studies in rats (OECD 407 and 421) indicate a significant absorption by the oral route.

Therefore, according to the REACH Guidance, a default value of 100% oral absorption will be used for risk assessment of the registered substance.

Inhalation route

The registered substance has a low volatility, its vapour pressure is 15.6 Pa at 25°C. As any highly lipophilic and poorly soluble in water compounds, the registered substance may be taken up by micellular solubilisation.

Therefore, according to the REACH Guidance, a default value of 100% inhalation absorption will be used for risk assessment of the registered substance.

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 between 1-100 mg/l absorption is anticipated to be low to moderate. Above a logP of 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.

The rate of absorption was estimated using the IH SkinPerm model using a Kp derived from the EPI Dermwin model. For an instantaneous deposition of 1000 mg over 1000 cm² of skin or a deposition over time of 1 mg/cm²/h, the absorption rates were 8% and 1%, respectively.

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

DISTRIBUTION

Once absorbed via the gastrointestinal tract it is likely that the registered substance will be distributed systemically into cells due to its lipophilic properties and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. No high first pass effect in the liver is expected due to lack of functional groups, which are only introduced by enzymatic reactions. According to the pkCSM method (Pires et al., 2015) for predicting small-molecule pharmacokinetic properties, the main components (S3, S4 and S5) of the registered substance are expected to have a low fraction unbound to serum proteins, and to readily cross the blood-brain barrier. 

	registered substance
	S3	S4	S5
Model Name	Predicted Value			Unit
Steady state volume of distribution (VDss human) (log L/kg)	0.287	0.29	0.296	VDss is considered low if below 0.71 L/kg (log VDss < -0.15) and high if above 2.81 L/kg (log VDss > 0.45)
Fraction unbound to serum proteins (human) (Fu)	0.188	0.159	0.126	the predicted fraction that would be unbound in plasma is calculated
Blood Brain Barrier (BBB) permeability (log BB)	0.74	0.732	0.721	a logBB > 0.3 is considered to readily cross the blood-brain barrier
CNS permeability (blood-brain permeability- surface area product, log PS)	-1.351	-1.424	-1.496	Compounds with a logPS > -2 are considered to penetrate the CNS, while those with logPS < -3 are considered as unable to penetrate the CNS

 

METABOLISM

In silico cytochrome P450 metabolism

The metabolism of the main components (S3, S4 and S5) of the registered substance by cytP450 was evaluated by the Xenosite P450 Metabolism 1.0 software. XenoSite is able to predict the site of metabolism (SOM) of a molecule for cytP4501A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 CYP isoforms. Xenosite computes a probability score varying between 0 and 1 (a high probability to be a SOM is characterized by a high score), which reflects both the confidence of the model that a particular atom is metabolised and the statistical likelihood that its prediction for that atom is correct, but they do not explicit model selectivity (which molecules are substrates of a given CYP enzyme). The disulphide bounds are the preferential sites of cytP450 metabolism of the main components (S3, S4 and S5) of the registered substance.

 

EXCRETION

The clearance rates by the pkCSM platform (Pires et al., 2015) of the main components (S3, S4 and S5) of the registered substance were predicted to be high but decreased as the molecular weight increase (1.76, 1.35 and 1.03 ml/min/kg).

Key value for chemical safety assessment

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100