Tetrakis(phenylmethyl)thioperoxydi(carbothioamide)

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

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: 100%

Type:

absorption

Results:

Absorption from gastrointestinal tract for 1000 mg dose: 90%

Conclusions:

Using a model to predict either high or low fraction absorbed for an orally administered, passively transported substance, the rates of absorption of TbzTD were 100 and 90% for a dose of 1 and 1000 mg, respectively (Danish QSAR).

Reference 2

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
-temperature : 25°C
-Molecular weight : 544 g/mol
-Vapour pressure : 0,85 Pa
-Water solubility : 0.01 mg/l
-Log kow : 3.7
-Density : 1100 mg/m3
-Melting point : 131 °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 %

Remarks on result:

other: Instantaneous deposition

Time point:

8 h

Dose:

1 mg/cm²/h

Parameter:

percentage

Absorption:

0 %

Remarks on result:

other: Deposition over time for 8 hr

Conclusions:

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

Executive summary:

The dermal absorption of TBzTD 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 (%)	0.00000416	0.00000026
Amount absorbed (mg)	0.0000416	0.0000416
Lag time stratum corneum (min)	2160
Max. derm. abs. (mg/cm²/h)	2.6 * 10^-9

Description of key information

Based on the physical and chemical properties, the QSAR predictions and the toxicological data available, TBzTD is considered as well absorbed by oral route and inhalation. However a low dermal route is predicted. 

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

Toxicokinetic of TBzTD is estimated based on the QSAR predictions and the physico-chemical properties.

Indeed, according to the REACH guidance document R7.C, information on absorption, distribution, metabolism and excretion may be deduced from the physicochemical properties, including:

-Molecular weight: 544 g/mol

-Water solubility: 0.01 mg/L (21°C)

-Partition coefficient Log Kow: 3.7

-Vapour pressure: 0.85 Pa (25°C)

 

ORAL ABSORPTION

With a log Kow closed to 4, a molecular mass higher than 500 g/mol and a low water solubility (< 1 mg/L), low oral absorption is expected.

However,using a model to predict either high or low fraction absorbed for an orally administered, passively transported substance, the rates of absorption of TBzTD were 100 and 90% for a dose of 1 and 1000 mg, respectively (Danish QSAR).

In the oral toxicity studies, no toxicity was observed after single exposure to 2000 mg/kg or repeated exposure to 1000 mg/kg (28 days).

Based on these data, 100% of oral absorption is used for risk assessment.

 

DERMAL ABSORPTION

With a water solubility below than 1, dermal absorption is anticipated to be low.

According to the IH skin perm (QSAR), the dermal absorption of TBzTD is estimated to be low (< 10%).

TBzTD is not a skin sensitizer.

Based on these data, 10% of dermal absorption is used for risk assessment.

 

INHALATION ABSORPTION

TBzTD is a solid with a low vapour pressure (< 1 Pa). The substance is not considered as a volatile substance.

100% of inhalation absorption is used for risk assessment.

 

DISTRIBUTION

As a small water-sluble substance, TBzTD is expected to be diffuse through aqueaous channels and pores.

Moreover, with a Log kow >0, TbzTD is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues.

 

METABOLISM

No data is available.

 

ELIMINATION

With a molecular weight of 544 g/mol, urinary excretion is not expected for TBzTD. Excretion in biles and in feces is probable.