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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:
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: 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.
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 TMTM were 50% for both doses of 1 and 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:
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: 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.

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.


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 feces is expected.


 


 


Route: .live2