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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%
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:
other: REACH Guidance on QSARs R.6
Qualifier:
according to
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)

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:
other: REACH Guidance on QSARs R.6
Qualifier:
according to
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.

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:
other: REACH Guidance on QSARs R.6
Qualifier:
according to
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 di-tert-butyl polysulphide.

ABSORPTION

The assessment of the toxicokinetics of di-tert-butyl polysulphide 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, di-tert-butyl polysulphide is expected to be well absorbed by the respiratory and gastro-intestinal tracts. Limited absorption is expected through the skin.

Oral route

Di-tert-butyl polysulphide 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), di-tert-butyl polysulphide 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 di-tert-butyl polysulphide 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 di-tert-butyl polysulphide.

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 di-tert-butyl polysulphide.

Inhalation route

Di-tert-butyl polysulphide is a substance with a low volatility, its vapour pressure is 15.6 Pa at 25°C. As any highly lipophilic and poorly soluble in water compounds, di-tert-butyl polysulphide 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 di-tert-butyl polysulphide.

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 di-tert-butyl polysulphide.

DISTRIBUTION

Once absorbed via the gastrointestinal tract it is likely that di-tert-butyl polysulphide 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 di-tert-butyl polysulphide substance are expected to have a low fraction unbound to serum proteins, and to readily cross the blood-brain barrier. 

 

Di-tert-butyl polysulphide

 

 

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 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). The disulphide bounds are the preferential sites of cytP450 metabolism of the main components (S3, S4 and S5) of di-tert-butyl polysulphide.

EXCRETION

The clearance rates by the pkCSM platform (Pires et al., 2015) of the main components (S3, S4 and S5) of di-tert-butyl polysulphide 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

Additional information


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