1,3-di-o-tolylguanidine

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(Nc(c(ccc1)C)c1)Nc(c(ccc2)C)c2

Type:

absorption

Results:

Intestinal absorption (human): 84.7%

Type:

distribution

Results:

VDss (human) (log L/kg): 2.227

Type:

distribution

Results:

Fraction unbound (human) : 0.354

Type:

distribution

Results:

BBB permeability (log BB): 0.258

Type:

distribution

Results:

CNS permeability (log PS): -0.922

Type:

excretion

Results:

Renal OCT2 substrate: yes

Type:

excretion

Results:

Total Clearance (log ml/min/kg): 0.802

Details on absorption:

According to the model "Intestinal absorption (human)", 84.7% 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 high (Log >> 0.45).
According to the model "Fraction unbound (human)", 35.4% 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 able to penetrate the CNS (log PS > -2).

Details on excretion:

According to the model "Renal OCT2 substrate", the substance is a OCT2 substrate. The substance is transported by this renal transporter.
According to the model "Total clearance" , the predicted total clearance (hepatic & renal clearance) is of 6.34 ml/min/kg (log(ml/min/kg) 0.802) corresponding to a moderate clearance (between 6 and 14 ml/min/kg).

Metabolites identified:

no

Conclusions:

According to the QSAR pkCSM, the substance is well absorbed by oral route (84.7%), well distributed into the body including the the brain, and probably excreted in the urines.

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:

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 DOTG were 100% and 90% % for 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: 239 g/mol
Temperature: 25 °C
Vapour Pressure: 0.00001 Pa
Water solubility: 70 mg/L
Log Kow: 2.9
Density: 286 mg/cm3
Melting point: 175°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:

0.891 %

Remarks on result:

other: Instantaneous deposition

Time point:

8 h

Dose:

1 mg/cm²/h

Parameter:

percentage

Absorption:

0.056 %

Remarks on result:

other: Deposition over time for 8 hr

Conclusions:

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

Executive summary:

The dermal absorption of DOTG 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 (%)	0.891	0.0557
Amount absorbed (mg)	8.91	8.91
Lag time stratum corneum (min)	32
Max. derm. abs. (mg/cm²/h)	0.000557

Description of key information

No experimental toxicokinetic study is available on 1,3 -di-o-totylguanidine (DOTG).

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 DOTG is expected to be high by oral route and inhalation, but low by dermal route. A good distribution and an excretion in the urines of DOTG 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 DOTG. 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: 239 g/mol

-Water solubility: 70 mg/L

-Partition coefficient Log Kow: 2.9

-Vapour pressure: 0.00001 Pa

 

ABSORPTION

Oral absorption

The physicochemical characteristics of DOTG (log Kow = 2.9) and the molecular mass (239 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 DOTG were 90-100% for both doses of 1 and 1000 mg (Danish QSAR). According to the model "Intestinal absorption (human)" (pkCSM), 84,7 % of the substance is absorbed after oral exposure.

This assumption of an oral absorption is confirmed in the acute toxicity study in rats: mortalities were observed at doses of 60 and 120 mg/kg, DOTG is toxic by oral route with a LD50 of 56 mg/kg bw in females.

100% of oral absorption in taken into account for risk assessment.

 

Dermal absorption

With a moderate water solubility (70 mg/L) and the low molecular mass (239 g/mol), dermal absorption is anticipated to be moderate to high.

The dermal absorption of DOTG is estimated to be low (<= 10%) according to the IH skin Perm (QSAR).

DOTG is not a skin sensitizer. Moreover, no systemic effect was observed in the dermal acute study at the maximal dose of 2000 mg/kg.

10% of dermal absorption in taken into account for risk assessment.

 

Inhalation absorption

Based on the low vapour pressure, DOTG 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 DOTG 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 DOTG is high, 35% of the absorbed dose is unbound in the plasma, the substance is able moderately to cross the blood-brain barrier and able to penetrate the CNS.

 

METABOLISM

No data on metabolism is available.

 

ELIMINATION

Due to the low molecular weight, DOTG could be excreted in the urines.

Indeed, according to the model "Renal OCT2 substrate" (pkCSM), the substance is a OCT2 substrate : DOTG is transported by this renal transporter.

The predicted total clearance (hepatic & renal clearance) is of 6 ml/min/kg corresponding to the low clearance.