Ethyl 4-dimethylaminobenzoate

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: 193.24 g/mol
Temperature: 25 °C
Vapour Pressure: 0.593 Pa
Water solubility: 77 mg/L
Log Kow:3.2
Density: 684.9 mg/cm3
Melting point: 63.9°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:

3.33 %

Remarks on result:

other: Instantaneous deposition

Time point:

8 h

Dose:

1 mg/cm²/h

Parameter:

percentage

Absorption:

0.208 %

Remarks on result:

other: Deposition over time for 8 hr

Conclusions:

The dermal absorption of Ethyl 4-dimethylaminobenzoate is estimated to be < 10%

Executive summary:

The dermal absorption of Ethyl 4-dimethylaminobenzoate 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 (%)	3.33	0.208
Amount absorbed (mg)0.	33.3	33.3
Lag time stratum corneum (min)	12.7
Max. derm. abs. (mg/cm²/h)	0.00208

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 valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

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: 95%

Type:

absorption

Results:

Absorption from gastrointestinal tract for 1000 mg dose: 90%

Conclusions:

According to this QSAR, 90-95% of the substance is absorbed after oral exposure.

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: CCOC(=O)C1=CC=C(C=C1)N(C)C

Type:

absorption

Results:

Intestinal absorption (human): 98.06 %

Type:

distribution

Results:

VDss (human) (log L/kg): 0.012

Type:

distribution

Results:

Fraction unbound (human) : 0.402

Type:

distribution

Results:

BBB permeability (log BB): 2.265

Type:

distribution

Results:

CNS permeability (log PS): -2.265

Type:

excretion

Results:

Renal OCT2 substrate: no

Type:

excretion

Results:

Total Clearance (log ml/min/kg): 0.719

Details on absorption:

According to the model "Intestinal absorption (human)", 98 % 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)", 40.2% 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 close to 0.3).
According to the model "CNS permeability", it is not possible to predict if the substance is unable or not to penetrate the CNS (-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 5.2 ml/min/kg (log(ml/min/kg) 0.719) corresponding to a 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 low total clearance is expected.

Description of key information

No experimental toxicokinetic study is available on Ethyl 4-dimethylaminobenzoate.

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 Ethyl 4-dimethylaminobenzoate is expected to be high by oral route and inhalation, but low by dermal route. A good distribution and excretion of the substance are 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 toxicokinetic study is available on Ethyl 4-dimethylaminobenzoate. However, as per REACH guidance document R7.C, information on absorption, distribution, metabolism and excretion may be deduced from the physical-chemical properties, including:

-Mean molecular weight: 193 g/mol

-Water solubility: 77 mg/L

-Partition coefficient Log Kow: 3.2

-Vapour pressure: 0.593 Pa (25°C)

 

ABSORPTION

The moderate values of log Kow and the water solubility of Ethyl 4-dimethylaminobenzoate are favorable for a moderate oral absorption. In the experimental studies, no clinical effects or mortality were observed after one single administration (2000 mg/kg) of Ethyl 4-dimethylaminobenzoate by gavage (oral route) in rats, however in the 28-day repeated toxicity study, clear systemic toxicity was noted at 900 mg/kg/day.

Using a model to predict either high or low fraction absorbed for an orally administered, passively transported substance, the rates of absorption of Ethyl 4-dimethylaminobenzoate were 95 and 90% for a dose of 1 and 1000 mg, respectively (Danish QSAR). According to the model "Intestinal absorption (human)", 98% of the substance is absorbed (pkCSM).

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

 

The moderate values of log Kow and the water solubility of Ethyl 4-dimethylaminobenzoate, and the molecular weight below than 500 g/mol are favorable for a moderate dermal absorption.

In the experimental studies, no dermal toxicity was noted: no mortality or toxicity observed in the acute study by dermal route in rats, and Ethyl 4-dimethylaminobenzoate is not a skin sensitizer.

According to the IH skin perm (QSAR), the dermal absorption of Ethyl 4-dimethylaminobenzoate is below 10%.That's why 10% of absorption is taken into account for the risk assessment.

 

Based on the low vapour pressure, Ethyl 4-dimethylaminobenzoate is considered to be not a volatile substance. However 100% of inhalation absorption is taken into account for the risk assessment (worst case).

 

DISTRIBUTION

No specific data is available on the distribution of Ethyl 4-dimethylaminobenzoate.

According to the QSAR pkCSM, the substance is well distributed into the body.

 

Specific organ toxicity on spleen and testes was observed in the 28 -day repeated toxicity study at the maximal dose of 900 mg/kg/day confirming the good distribution of the substance into the body.

 

 

METABOLISM

There are no experimental study on metabolism of Ethyl 4-dimethylaminobenzoate

 

ELIMINATION

Due to the low water solubility, the excretion of Ethyl 4-dimethylaminobenzoate in the urines is expected to be low. An excretion via bile and faeces is possible.

According to the QSAR pkCSM, a low total clearance (hepatic & renal) is expected.