5,5'-dithiodi-1,3,4-thiadiazole-2(3H)-thione

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

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=C1NN=C(SSC2=NNC(=S)S2)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.

Reference 2

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:

accepted calculation method

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): S=C1NN=C(SSC2=NNC(=S)S2)S1

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).

Reference 3

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 studies involving repeated exposure via the oral route.
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 %. Consequently, 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 as a default value and in the absence of experimental data.

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 animal studies involving a repeated exposure.
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 after absorption. Based on 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.