2-isopropyl-9H-thioxanthen-9-one

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

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: 254 g/mol
Temperature: 20 °C
Vapour Pressure: 0.00003 Pa
Water solubility: 0.34 mg/L
Log Kow: 5.59
Density: 732 mg/cm3
Melting point: 75°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:

0.317 %

Remarks on result:

other: Instantaneous deposition

Time point:

8 h

Dose:

1 mg/cm²/h

Parameter:

percentage

Absorption:

0.02 %

Remarks on result:

other: Deposition over time for 8 hr

Conclusions:

The dermal absorption of 2-Isopropylthioxanthone is estimated to be < 10%

Executive summary:

The dermal absorption of 2-Isopropylthioxanthone 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 (%)	0.317	0.0198
Amount absorbed (mg)0.	3.17	3.17
Lag time stratum corneum (min)	6.26
Max. derm. abs. (mg/cm²/h)	0.000198

Reference 2

Endpoint:

basic toxicokinetics, other

Remarks:

G.I. human passive absorption

Type of information:

calculation (if not (Q)SAR)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

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): c12C(=O)c3c(ccc(C(C)C)c3)Sc1cccc2

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: 50%

Conclusions:

Using a model to predict either high or low fraction absorbed for an orally administered, passively transported substance, the rates of absorption were 100% and 50% for a dose of 1 and 1000 mg respectively (Danish (Q)SAR Database).

Reference 3

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:

SMILE : c12C(=O)c3c(ccc(C(C)C)c3)Sc1cccc2

Type:

absorption

Results:

Intestinal absorption (human): 96.12%

Type:

distribution

Results:

VDss (human) (log L/kg): 0.274

Type:

distribution

Results:

Fraction unbound (human) : 0.07

Type:

distribution

Results:

BBB permeability (log BB): 0.627

Type:

distribution

Results:

CNS permeability (log PS): -1.212

Type:

excretion

Results:

Renal OCT2 substrate: no

Type:

excretion

Results:

Total Clearance (log ml/min/kg): -0.044

Details on absorption:

According to the model "Intestinal absorption (human)", 96 % 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)", 7% of the absorbed dose is unbound in the plasma.
According to the model "BBB permeability", the substance is cross readily the blood-brain barrier (log BB > 0.3).
According to the model "CNS permeability", the substance is considered to penetrate the Central Nervous System (CNS) (log PS > -2).

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 0.9 ml/min/kg (log(ml/min/kg) -0.044) corresponding to a very low clearance.

Metabolites identified:

no

Conclusions:

According to the QSAR pkCSM, the substance is well absorbed by oral route, and well distributed into the body. Moreover, a very low total clearance is expected.

Description of key information

No experimental studies of the absorption, distribution, metabolism or elimination on 2-Isopropylthioxanthone are available. However, the physical chemical properties, the QSAR prediction and the existing toxicology studies on the substance have been used to predict its potential toxicokinetics.

After oral exposure, a high absorption and a good distribution is expected for 2-Isopropylthioxanthone. However a low dermal absorption is expected.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

No experimental studies of the absorption, distribution, metabolism or elimination on 2-Isopropylthioxanthone are available. However, the physical chemical properties, the QSAR prediction and the existing toxicology studies on the substance have been used to predict its potential toxicokinetics.

The substance 2-Isopropylthioxanthone is a mono-constituent substance. It is a cream to pale yellow powder, with a median particle size D50 of 369 µm, D10 of 106 µm and D90 of 829 µm. Its molecular weight (MW) is 254.347 g/mol. The substance is very poorly water-soluble (0.34 mg/L at 20 °C), and its partition coefficient (Log Kow/Log Pow) is 5.59. The vapour pressure was determined to be 3 x 10^-5 Pa at 20 °C.

 

Oral Absorption

The very low water-solubility and high Log Pow would limit the rate of absorption from the gut; the molecular weight slightly greater than 200 also indicates that passage through aqueous pores or transport through the epithelial barrier by the bulk passage of water are unlikely. However, micellar solubilisation may be of particular importance for absorption mainly in the small intestine.

Using a model to predict either high or low fraction absorbed for an orally administered, passively transported substance, the rates of absorption were 100% and 50% for a dose of 1 and 1000 mg respectively (Danish (Q)SAR Database). According to the QSAR pkCSM, the substance is well absorbed by oral route (96%).

The results of the acute oral studies in rats, with the no mortality or clinical signs at 2000 mg/kg, confirm a limited absorption. However, under repeated oral dosing regimen, effects mainly on the liver were observed in the repeated dose toxicity studies in rats, confirming the oral absorption.

Based on this information, it is clear that significant oral absorption is likely : an oral absorption of 100% is taken into account for human health risk assessment purposes.

 

Dermal Absorption

Although 2-Isopropylthioxanthone is not an excessively large molecule, it is a solid, and the extremely low water solubility (0.34 mg/L at 20 °C) and high Log Pow (5.59) indicate that dermal uptake will be low, and the rate of transfer between the stratum corneum and the epidermis will be slow. This is supported by the acute dermal toxicity study in rats, where no mortality or clinical signs at 2 000 mg/kg. In addition, the substance is not irritating to the rabbit skin, and not skin sensitising in guinea pigs.

According to the IH SkinPerm prediction (QSAR), the dermal absorption of 2-Isopropylthioxanthone is estimated to be < 10%.

A dermal absorption of 10% is taken into account for human health risk assessment purposes.

 

Inhalation Absorption

Particle size distribution of 2-Isopropylthioxanthone indicates the substance is too large for reaching the respiratory system. In addition, the very low vapour pressure (6.1 x10-5Pa at 25 °C) indicates that the substance cannot generate an inhalable vapour. The extremely low water-solubility suggests that any inhaled particles reaching the upper respiratory tract could be coughed or sneezed out of the body or swallowed. In the absence of any quantitative data, and in accordance with ECHA guidance, for human health risk assessment purposes absorption by inhalation of 2-Isopropylthioxanthone is assumed to be 100 %.

 

Distribution

The available repeat-dose oral toxicity studies in rats identified the liver as the main target organ. The relatively low molecular weight of the substance would suggest wider distribution although this might be countered by the low water solubility. The Log Pow value suggests that the intracellular concentration may be higher than extracellular concentration.

According to the QSAR pkCSM, the substance is well distributed into the body, including in the central nervous system.

 

Metabolism

The two 28-day repeated dose toxicity studies in rats showed increases of liver weight accompanied by hepatocellular hypertrophy, suggesting hepatic enzyme induction and enhanced liver metabolism following oral administration of 2-Isopropylthioxanthone.

 

Excretion

The low molecular weight would suggest prevalence of urinary excretion in case conjugated metabolites are formed. No notable kidney weight changes were observed in the available 28-day repeated dose toxicity studies in rats; biliary excretion may well be another route of excretion for this poorly water-soluble substance.

According to the QSAR pkCSM, a very low total clearance is expected with 2-Isopropylthioxanthone.