Tetramethylthiuram monosulphide

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: N(C(=S)SC(N(C)C)=S)(C)C

Type:

absorption

Results:

Intestinal absorption (human): 90.711%

Type:

distribution

Results:

VDss (human) (log L/kg): -0.036

Type:

distribution

Results:

Fraction unbound (human) : 0.669

Type:

distribution

Results:

BBB permeability (log BB): 0.05

Type:

distribution

Results:

CNS permeability (log PS): -3.102

Type:

excretion

Results:

Renal OCT2 substrate: no

Type:

excretion

Results:

Total Clearance (log ml/min/kg): 0.498

Details on absorption:

According to the model "Intestinal absorption (human)", 90% 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)", 66.9% of the absorbed dose is unbound in the plasma.
According to the model "BBB permeability", the substance is able moderately to cross the blood-brain barrier (Log BB between -1 and 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 3.14 ml/min/kg (log(ml/min/kg) 0.498) corresponding to the very low clearance (below 6 ml/min/kg).

Metabolites identified:

no

Property	Model Name	Predicted Value	Unit
Absorption	Water solubility	-1.958	Numeric (log mol/L)
Absorption	Caco2 permeability	1.408	Numeric (log Papp in 10^-6cm/s)
Absorption	Intestinal absorption (human)	90.711	Numeric (% Absorbed)
Absorption	Skin Permeability	-2.521	Numeric (log Kp)
Absorption	P-glycoprotein substrate	YES	Categorical (Yes/No)
Absorption	P-glycoprotein I inhibitor	No	Categorical (Yes/No)
Absorption	P-glycoprotein II inhibitor	No	Categorical (Yes/No)
Distribution	VDss (human)	-0.036	Numeric (log L/kg)
Distribution	Fraction unbound (human)	0.669	Numeric (Fu)
Distribution	BBB permeability	0.05	Numeric (log BB)
Distribution	CNS permeability	-3.102	Numeric (log PS)
Metabolism	CYP2D6 substrate	NO	Categorical (Yes/No)
Metabolism	CYP3A4 substrate	NO	Categorical (Yes/No)
Metabolism	CYP1A2 inhibitior	NO	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	0.498	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 (80.8%), 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:

(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 TMTM were 50% for both doses of 1 and 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: 208 g/mol
Temperature: 25 °C
Vapour Pressure: 0.002 Pa
Water solubility: 308 mg/L
Log Kow: 1.17
Density: 600 mg/cm3
Melting point: 108°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:

0.36 %

Remarks on result:

other: Instantaneous deposition

Time point:

8 h

Dose:

1 mg/cm²/h

Parameter:

percentage

Absorption:

0.022 %

Remarks on result:

other: Deposition over time for 8 hr

Conclusions:

The dermal absorption of TMTM is estimated to be low (<= 10%).

Executive summary:

The dermal absorption of TMTM 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 (%)	0.36	0.0225
Amount absorbed (mg)	3.6	3.6
Lag time stratum corneum (min)	62.8
Max. derm. abs. (mg/cm²/h)	0.000225

Description of key information

No experimental toxicokinetic study is available on Tetramethylthiuram monosulfide (TMTM).

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, supported by observations recorded during animal testing.

Based on the physical-chemical properties and QSAR predictions, the absorption of TMTM is expected to be high by oral route and inhalation, but low by dermal route. A good distribution and an excretion in the feces of TMTM are expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

No experimental toxicokinetic study is available on TMTM. However, as per REACH guidance document R7.C, information on absorption, distribution, metabolism and excretion may be deduced from the physicochemical properties, including:
-Molecular weight: 208 g/mol
-Water solubility: 308 mg/L
-Partition coefficient Log Kow: 1.17
-Vapour pressure: 0.002 Pa

ABSORPTION
Oral absorption
The physicochemical characteristics of TMTM (log Kow = 1.17) and the molecular mass (208 g/mol) are in the range suggestive of absorption from the gastro-intestinal tract subsequent to oral ingestion (with a molecular weight below 500, and a log Kow between -1 and 4).
Using a model to predict either high or low fraction absorbed for an orally administered, passively transported substance, the rates of absorption of TMTM were 50% for both doses of 1 and 1000 mg (Danish QSAR). According to the model "Intestinal absorption (human)" (pkCSM), 90% of the substance is absorbed after oral exposure.
This assumption of an oral absorption is confirmed in the acute toxicity study in rats: clinical signs were observed at doses of 500 mg/kg and above, TMTM is harmful by oral route with a LD50 of 690 mg/kg bw. During animal studies involving a repeated exposure and conducted using the oral route of exposure, mottling of the liver was recorded, as well as necrosis and/or inflammation, thus confirming absorption occurred.
100% of oral absorption in taken into account for risk assessment.

Dermal absorption
With a moderate water solubility (308 mg/L) and the low molecular mass (208 g/mol), dermal absorption is anticipated to be moderate to high.
The dermal absorption of TMTM is estimated to be low (<= 10%) according to the IH skin Perm (QSAR).
Indeed TMTM is a skin sensitizer; it is evidence that some uptake must have occurred although it may only have been a small fraction of the applied dose. However, no systemic effect was observed in the dermal acute study.
10% of dermal absorption in taken into account for risk assessment.

Inhalation absorption
Based on the low vapour pressure, TMTM is considered to be not a volatile substance.
100% of inhalation absorption in taken into account for risk assessment.

DISTRIBUTION
As a small molecule, a wide distribution of TMTM is expected. Moreover, the molecule is lipophilic (log Kow > 0), it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues.
According to the models in pkCSM (QSAR), the volume of distribution of TMTM is moderate, 66.9% of the absorbed dose is unbound in the plasma, the substance is able moderately to cross the blood-brain barrier but unable to penetrate the CNS.

METABOLISM
According to the models in pkCSM (QSAR), TMTM is not a substrate or an inhibitor of the cytochrome P450.

ELIMINATION
Due to the low molecular weight, TMTM could be excreted in the urines, but TMTM has a poor water solubility.
However, according to the model "Renal OCT2 substrate" (pkCSM), the substance is not a OCT2 substrate. The substance is not transported by this renal transporter. The predicted total clearance (hepatic & renal clearance) is of 3.14 ml/min/kg corresponding to the very low clearance.
So, an excretion in the faeces is expected.