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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: S=C2SC(=NN2)SSC1=NNC(=S)S1
Type:
absorption
Results:
Intestinal absorption (human): 88.38%
Type:
distribution
Results:
VDss (human) (log L/kg): 0.044
Type:
distribution
Results:
Fraction unbound (human) : 0.634
Type:
distribution
Results:
BBB permeability (log BB): 0.242
Type:
distribution
Results:
CNS permeability (log PS): -3.911
Type:
excretion
Results:
Renal OCT2 substrate: no
Type:
excretion
Results:
Total Clearance (log ml/min/kg): -0.268
Details on absorption:
According to the model "Intestinal absorption (human)", 88.38% of the substance is absorbed after oral exposure.

Details on distribution in tissues:
According to the model "VDss (human)", the volume of distribution (VD, i.e. theoritical volume that the total dose of a drug would need to be uniformly distributed to give the same concentration as in blood plasma) is moderate (Log between -0.15 and 0.45).
According to the model "Fraction unbound (human)", 63.4 % of the absorbed dose is unbound in the plasma.
According to the model "BBB permeability", the substance is moderately cross the blood-brain barrier (0.1 < Log BB < 0.3).
According to the model "CNS permeability",the substance is unable to penetrate the CNS (log PS <-3).
Details on excretion:
According to the model "Renal OCT2 substrate", the substance is not a OCT2 substrate. The substance is not transported by this renal transporter.
According to the model "Total clearance" , the predicted total clearance (hepatic & renal clearance) is of 0.54 ml/min/kg (log(ml/min/kg) -0.268) corresponding to the very low clearance (below 6 ml/min/kg).
Metabolites identified:
no

Property

Model Name

Predicted Value

Unit

Absorption

Water solubility

-3.55

Numeric (log mol/L)

Absorption

Caco2 permeability

1.324

Numeric (log Papp in 10-6cm/s)

Absorption

Intestinal absorption (human)

88.382

Numeric (% Absorbed)

Absorption

Skin Permeability

-2.753

Numeric (log Kp)

Absorption

P-glycoprotein substrate

No

Categorical (Yes/No)

Absorption

P-glycoprotein I inhibitor

No

Categorical (Yes/No)

Absorption

P-glycoprotein II inhibitor

No

Categorical (Yes/No)

Distribution

VDss (human)

0.044

Numeric (log L/kg)

Distribution

Fraction unbound (human)

0.634

Numeric (Fu)

Distribution

BBB permeability

0.242

Numeric (log BB)

Distribution

CNS permeability

-3.911

Numeric (log PS)

Metabolism

CYP2D6 substrate

No

Categorical (Yes/No)

Metabolism

CYP3A4 substrate

No

Categorical (Yes/No)

Metabolism

CYP1A2 inhibitior

YES

Categorical (Yes/No)

Metabolism

CYP2C19 inhibitior

No

Categorical (Yes/No)

Metabolism

CYP2C9 inhibitior

No

Categorical (Yes/No)

Metabolism

CYP2D6 inhibitior

No

Categorical (Yes/No)

Metabolism

CYP3A4 inhibitior

No

Categorical (Yes/No)

Excretion

Total Clearance

-0.268

Numeric (log ml/min/kg)

Excretion

Renal OCT2 substrate

No

Categorical (Yes/No)

Conclusions:
According to the QSAR pkCSM, the substance is well absorbed by oral route (88.38%), and well distributed into the body. Moreover, no hepatic and renal clearance is expected.
Endpoint:
basic toxicokinetics, other
Remarks:
G.I. human passive absorption
Type of information:
calculation (if not (Q)SAR)
Adequacy of study:
weight of evidence
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.
Species:
other: Human
Route of administration:
oral: unspecified
Type:
absorption
Results:
Absorption from gastrointestinal tract for 1 mg dose: 50%
Type:
absorption
Results:
Absorption from gastrointestinal tract for 1000 mg dose: 50%
Conclusions:
Using a model to predict either high or low fraction absorbed for an orally administered, passively transported substance, the rates of absorption of 5,5'-dithiodi-1,3,4-thiadiazole-2(3H)-thione were 50% for a dose of 1 or 1000 mg (Danish QSAR).
Endpoint:
dermal absorption, other
Remarks:
QSAR
Type of information:
(Q)SAR
Adequacy of study:
key study
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: 142 g/mol
Temperature: 25 °C
Vapour Pressure: 12.6 Pa
Water solubility: 18.3 mg/L
Log Kow: 4.47
Density: 930 mg/cm3
Melting point: -94.8°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:
15.1 %
Remarks on result:
other: Instantaneous deposition
Time point:
8 h
Dose:
1 mg/cm²/h
Parameter:
percentage
Absorption:
0.94 %
Remarks on result:
other: Deposition over time for 8 hr
Conclusions:
The dermal absorption of 5,5'-dithiodi-1,3,4-thiadiazole-2(3H)-thione is estimated to be moderate.
Executive summary:

The dermal absorption of 5,5'-dithiodi-1,3,4-thiadiazole-2(3H)-thione 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

16000

Fraction absorbed (%)

15.1

 0.941

Amount absorbed (mg)

151

151

Lag time stratum corneum (min)

2.34

Max. derm. abs. (mg/cm²/h)

0.00941

Description of key information

No experimental toxicokinetic study is available on 5,5’-Dithiodi-1,3,4-thiadiazole-2(3H)-thione.

However, as per REACH guidance document R7.C , information on absorption, distribution, metabolism and excretion may be deduced from the physical-chemical properties and QSAR predictions.

Based on the physical-chemical properties and QSAR predictions, the absorption of 5,5’-Dithiodi-1,3,4-thiadiazole-2(3H)-thione is expected to be high by oral route and inhalation, but moderate by dermal route. A good distribution and excretion of the substance are expected.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

The physical-chemical properties of 5,5’-Dithiodi-1,3,4-thiadiazole-2(3H)-thione (CAS RN 72676-55-2):

• Molecular weight (MW): 298.45 g/mol

• Water solubility: 167 mg/L

• N-octanol/water partition coefficient (log P): 1.46

• Vapour pressure: 0.000041 Pa

Oral Absorption

The physicochemical characteristics of 5,5’-Dithiodi-1,3,4-thiadiazole-2(3H)-thione (log Pow of 1.46 and water solubility of 167 mg/L) and the molecular mass are in a range suggestive of absorption from the gastro-intestinal tract subsequent to oral ingestion. It is also projected to be orally bioavailable based on Lipinski's Rule. This assumption of oral absorption is confirmed by the systemic effects observed in the combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD TG 422).

Using a model to predict either low or high fraction absorbed for an orally administered, passively transported substance, the rates of absorption of 5,5'-dithiodi-1,3,4-thiadiazole-2(3H)-thione were 50% for a dose of 1 or 1000 mg (Danish QSAR). According to the model "Intestinal absorption (human)" (pkCSM), 88.38% of the substance is absorbed after oral exposure.

For the risk assessment, an oral absorption of 100% is taken into account.

Dermal Absorption

N-octanol/water partition coefficient and molecular weight of 5,5’-Dithiodi-1,3,4-thiadiazole-2(3H) -thione are in ranges which favor dermal absorption. Dermal absorption is inferred based upon the positive result in the skin sensitisation study in which 5,5’-Dithiodi-1,3,4-thiadiazole-2(3H)-thione is considered to be a skin sensitizer (OECD TG 429).

According to the IH skin perm (QSAR), the dermal absorption of 5,5’-Dithiodi-1,3,4-thiadiazole-2(3H) -thione is between 1% and 15 %.That's why 50% of absorption is taken into account for the risk assessment.

Inhalation absorption

No absorption by inhalation is expected due to the low vapour pressure of 5,5’-Dithiodi-1,3,4-thiadiazole-2(3H) –thione.

However, 100% of absorption is taken into account for the risk assessment.

Distribution and Metabolism

As a small molecule (MW<500 g/mol), a wide distribution is expected. This assumption is confirmed by the test substance or its metabolites (brown/yellow pigment) observed in the renal tubular epithelial cells and the systemic effects shown in the combined repeated dose toxicity study following oral administration.

According to the QSAR pkCSM, the substance is well distributed into the body.

Elimination

The rapid hydrolytic degradation at all pH and the n-octanol/water partition coefficient (log Pow 1.46) of 5,5’-Dithiodi-1,3,4-thiadiazole-2(3H)-thione suggest that the potential for accumulation in fatty tissues is very limited subsequent to absorption. On the basis of the molecular structure excretion into urine is assumed to be a preferred route of elimination. This assumption is confirmed by the observation of the test substance or its metabolites (brown/yellow pigment) in the renal tubular epithelial cells in the combined repeated dose toxicity study. Elimination is assumed to be rapid. Therefore, no potential for bioaccumulation is expected.

According to the QSAR pkCSM, no hepatic and renal clearance is expected.

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