butanedioic acid, 2-octenyl

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Study period:

2017

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:

1. SOFTWARE: ADMET predictor and GastroPlus

2. MODEL (incl. version number): ADMET predictor (v7.2, Simulations Plus Inc, Lancaster, CA, USA) and GastroPlus (v9.0, Simulations Plus Inc, Lancaster, CA, USA)

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL: Octenysuccinic acid SMILES code
SMILES code: O=C(O)C(C\C=C\CCCCC)CC(=O)O

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL:
Endpoint (OECD Principle 1):
Endpoint:
i. The absorption fraction (Fa%) of octenylsuccinic acid following oral, dermal, and inhalation exposures in humans.
ii. Systemic bioavailability (F%), Cmax, Tmax, and AUC0-168 of octenylsuccinic acid following oral, dermal, and inhalation exposures in humans.
iii. The plasma protein binding and volume of distribution (Vd).
iv. The potential metabolism and excretion of octenylsuccinic acid in human.

Algorithm (OECD Principle 2):
a. Model or submodel name: For the prediction of Fa%, F%, Cmax, Tmax, and AUC 0-168 of octenylsuccinic acid, a PBPK model was utilized in GastroPlus (version 9) to simulate absorption parameters and systemic bioavailability of octenylsuccinic acid following a single oral (or inhalation or dermal) dose of 1 mg/kg.bw in a fed 30-year old human (70 kg). The oral dose formulation type was defined to be a suspension with particle size of 50 µm mean diameter. This particle size was selected based on oral PSA (parameter sensitivity analysis) simulation results of Fa% and F% versus the particle size ranging from of 2.5 µm to 250 µm with GastroPlus; for octenylsuccinic acid, particle size did not affect absorption. The oral absorption in GastroPlus utilizes the Advanced Compartmental Absorption and Transit (ACAT) model to predict passive absorption across the gut and accounts for soluble and insoluble portions of the administered dose. The inhalation dose formulation type was defined to be a powder with a particle size of 2.5 µm mean diameter. This particle was selected based on the Concawe report (Hext, et al., 1999). Particle size of 2.5 µm or less are considered the fine fraction and are associated with a higher risk of health effects. These smaller particles are considered the highly respirable fraction of a particulate atmosphere and can reach the deep alveolar regions of the lung. In the current GastroPlus simulation, the inhalation dose was delivered over 8-hr period. This implementation of the inhalation include up to five (5) compartments: an optional nose, extrathoracic, thoracic, bronchiolar, and alveolar-interstitial. The deposition fractions for each compartment were generated with a built-in predictive model based on the International Comission for Radiological Protection Publication 66 ( ICRP 66) deposition model described in GastroPlus. The dermal dose formulation type was defined to be a water suspension with particle size of 50 µm mean diameter. This particle size was selected based on the dermal PSA (parameter sensitivity analysis) simulation results of Fa% and F% versus the particle size ranging from of 2.5 µm to 250 µm with GastroPlus. Again, particle size did not affect absorption across this particle size range. The dermal absorption simulation model in GastroPlus represents the skin as a collection of the following compartments: stratum corneum, viable epidermis, dermis, subcutaneous tissue, sebum, hair lipid, and hair core. The application surface is 1900 cm2 on human arm. The dose volume and exposure time were 19 mL, and 6 hrs, respectively. This surface area, dose volume, and expose time were selected based on the US EPA dermal exposure assessment report (US EPA, 1992). Bioavailability predictions for these three exposure routes were made by including metabolism by five major cytochrome (CYP) P450 enzymes (1A2, 2C9, 2C19, 2D6, and 3A4) in human. These QSAR predictions of metabolic clearance [(enzyme kinetics (Km and Vmax) based on recombinant CYP enzymes] were generated using ADMET Predictor (v7.2, Simulations Plus Inc, Lancaster, CA, USA) from the structure of octenylsuccinic acid.
The plasma protein binding and volume of distribution (Vd) were predicted by ADMET Predictor (v7.5, Simulations Plus Inc, Lancaster, CA, USA).
The metabolism and excretion of octenylsuccinic acid was proposed based on the CYP metabolism in human predicted by ADMET predictor.

b. Model version: GastroPlus v9.0 (Simulations Plus Inc, Lancaster, CA, USA); ADMET Predictor v7.2 (Simulations Plus Inc, Lancaster, CA, USA).
GastroPlus is a physiologically based pharmacokinetic (PBPK) modeling and simulation software package that simulates intravenous, oral, oral cavity, ocular, inhalation, and dermal/subcutaneous absorption, pharmacokinetics, and pharmacodynamics in human and animals. It was developed for use by the pharmaceutical industry and is licensed for use by most top 25 pharmaceutical companies in the USA and Europe. Within GastroPlus, the ACAT™ (Advanced Compartmental Absorption and Transit) model has been refined numerous times since its inception in 1997 to provide accurate, flexible, and powerful simulations. ADMET Predictor is used for advanced predictive modelling of ADMET properties. The "ADMET" acronym is commonly used in the pharmaceutical industry to indicate all the phenomena associated with Absorption, Distribution, Metabolism, Elimination, and Toxicity of chemical substances in the human body.

Input for prediction: SMILES codes:
octenylsuccinic acid: O=C(O)C(C\C=C\CCCCC)CC(=O)O

5. APPLICABILITY DOMAIN:
Descriptor values: Applicability domain (OECD principle 3):
Domains: Defined by GastroPlus and ADMET Predictor.
i. Descriptor domain: In general, ADMET Predictor and GastroPlus apply only to small organic molecules composed of the following elements: C, N, O, S, P, H, F, Cl, Br, I, B and their isotopes. Other elements (in particular metals) are not supported. In addition, the program limits the size and complexity of input molecules to no more than 256 bonds and no more than 20 ionizable groups. Octenylsuccinic acid meets these GastroPlus/ADMET predictor criteria.
ii. Structural fragment domain: ADMET Predictor and GastroPlus use calculated descriptors for each chemical structure as inputs to its predictive models; it does not use structural fragments
iii. Mechanism domain: ADMET Predictor and GastroPlus models use QSAR/QSPR (quantitative structure-activity relationship/ quantitative structure-property relationship) methodology, which is a subset of statistical-correlative modelling. It does not consider mechanisms of action, at least not explicitly.
iv. Metabolic domain: Metabolism is considered relevant and is considered in the assessment as part of the GastroPlus/ADMET predictor modeling.

6. ADEQUACY OF THE RESULT:
Regulatory purpose: The predicted information is adequate to support hazard characterization (classification and labeling) as well as chemical risk assessment.
Approach for regulatory interpretation of the model result: The oral, dermal, and inhalation Fa% and F% of octenylsuccinic acid are predicted by the GastroPlus QSAR program. The plasma protein binding and volume of distribution (Vd) of octenylsuccinic acid are predicted by ADMET Predictor. The potential metabolism and excretion of octenylsuccinic acid are proposed according to human CYP metabolism predicted by ADMET Predictor.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Qualifier:

no guideline followed

Version / remarks:

QSAR Prediction Reporting Format (QPRF) v 1.1

Principles of method if other than guideline:

To assess the ADME potential of octenylsuccinic acid in humans, the widely accepted QSAR programs, ADMET predictor (v7.2, Simulations Plus Inc, Lancaster, CA, USA), and GastroPlus (v9.0, Simulations Plus Inc, Lancaster, CA, USA) were used.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

butanedioic acid, 2-octenyl

EC Number:

820-780-3

Cas Number:

62568-82-5

Molecular formula:

C12 H20 O4

IUPAC Name:

butanedioic acid, 2-octenyl

Test material form:

other: SMILES: O=C(O)C(C\C=C\CCCCC)CC(=O)O

Remarks:

Information on Chemical structure and SMILES for the test material used for QSAR.

Specific details on test material used for the study:

CAS number: 62568-82-5
Chemical name: Octenylsuccinic acid
SMILES: O=C(O)C(C\C=C\CCCCC)CC(=O)O

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Predicted Fractional Absorption (Fa%): oral: 98.8%, dermal:94.4%, Inhalation:81.1%; Predicted Systemic Bioavailability (F%): oral: 98.7%, dermal:2.12%, Inhalation:81.1%; Predicted Cmax (µg/mL) : oral: 5.43, dermal:0.00763, Inhalation: 3.84;

Main ADME results 2

Type:

distribution

Results:

The predicted human plasma protein binding upon absorption for octenylsuccinic acid is 85.4%. The volume of distribution in humans was estimated to be low (11.2 L, 0.16 L/kg), which indicates low distribution to body tissues.

Main ADME results 3

Type:

metabolism

Results:

ADMET predictor: Octenylsuccinic acid will be metabolized to its hydroxylated metabolites (by human CYP 2C19). The formed hydroxylated metabolites can be further metabolized to water soluble metabolites (such as glucuronides and sulfates)

Main ADME results 4

Type:

excretion

Results:

The various conjugate forms (such as sulfates, glucuronides) of the proposed metabolites would be more water-soluble than the parent compound; therefore, these metabolites would be expected to be excreted in urine and faeces.

Main ADME results 5

Type:

other: Accumulation

Results:

On the basis of low volume of distribution, octenylsuccinic acid is not expected to bioaccumulate.

Any other information on results incl. tables

Predicted value (model result):  

Absorption:  The PSA simulation results showed that both Fa% and F% were not impacted by particle sizes ranging from 2.5 µm to 250 µm in either oral exposure or dermal exposure; therefore 50 µm diameter particle size was applied for both oral and dermal simulations. At 1 mg/kg exposure dose level in a fed 30-year old human (70 kg), the predicted fractional absorption (Fa%) values for oral, dermal, and inhalation exposures to octenylsuccinic acid in humans by GastroPlus are 98.8%, 94.4%, and 81.1%, respectively.  The predicted systemic bioavailability (F%) values for octenylsuccinic acid from oral, dermal, and inhalation exposures are 98.7%, 2.12%, and 81.1%, respectively; the predicted Cmax values are 5.43, 0.00763, and 3.84 µg/mL respectively.  At the dermal exposure level of 100 mg/kg, the predicted Cmax is only 0.753 µg/mL, indicating that at least 500 mg/kg dermal exposure level is required to produce the oral Cmax level of 5.43 µg/mL.

Distribution:  The predicted human plasma protein binding upon absorption for octenylsuccinic acid is 85.4%.  Higher protein binding values generally indicate lower bioavailability to interact with other target sites.  The volume of distribution in humans was estimated to be low (11.2 L, 0.16 L/kg), which indicates low distribution to body tissues.

Accumulation: On the basis of low volume of distribution, octenylsuccinic acid is not expected to bioaccumulate

Metabolism:  Based on the metabolism prediction by ADMET predictor, octenylsuccinic acid will be metabolized to its hydroxylated metabolites (by human CYP 2C19).  The formed hydroxylated metabolites can be further metabolized to water soluble metabolites (such as glucuronides and sulfates).

Excretion: The various conjugate forms (such as sulfates, glucuronides) of the above proposed metabolites would be more water-soluble than the parent compound; therefore, these metabolites would be expected to be excreted in urine and faeces.

Applicant's summary and conclusion

Conclusions:

At 1 mg/kg exposure dose level in a fed 30-year old human (70 kg), the predicted fractional absorption (Fa%) values of oral, dermal, and inhalation for
octenylsuccinic acid in humans by GastroPlus are 98.8%, 94.4%, and 81.1%, respectively. The predicted systemic bioavailability (F%) values for octenylsuccinic acid from oral, dermal, and inhalation exposures are 98.7%, 2.12%, and 81.1%, respectively; the predicted Cmax values are 5.43, 0.00763, and 3.84 μg/mL respectively. At the dermal exposure level of 100 mg/kg, the predicted Cmax is only 0.753 μg/mL, indicating that at least 500 mg/kg dermal exposure level is required to produce the oral Cmax level of 5.43 μg/mL. The low F%, but high Fa% values for dermal exposure, are mainly due to the fact that octenylsuccinic acid is mainly absorbed in the stratum corneum of skin and cannot get into blood circulation in blood. The predicted human plasma protein binding upon absorption for octenylsuccinic acid by any exposure route is 85.4%. The volume of distribution in humans was estimated to be low (11.2 L, 0.16 L/kg).
Based on the metabolism prediction by ADMET predictor, octenylsuccinic acid will be metabolized to the hydroxylated metabolites (by human CYP 2C19). The
formed hydroxylated metabolites can also be further metabolized to water soluble metabolites (such as glucuronides and sulfates), which will be mainly excreted into urine and feces.
On the basis of low volume of distribution, and predicted metabolism and excretion, octenylsuccinic acid is not expected to bioaccumulate in humans.

Executive summary:

Experimental data on absorption, distribution, metabolism and excretion (ADME) are not available for octenylsuccinic acid. To assess the ADME potential of octenylsuccinic acid in humans, the widely accepted QSAR programs, ADMET predictor (v7.2, Simulations Plus Inc, Lancaster, CA, USA), and GastroPlus (v9.0, Simulations Plus Inc, Lancaster, CA, USA) were used. 

At 1 mg/kg exposure dose level in a fed 30-year old human (70 kg), the predicted fractional absorption (Fa%) values for oral, dermal, and inhalation exposures to octenylsuccinic acid in humans by GastroPlus are 98.8%, 94.4%, and 81.1%, respectively; the predicted systemic bioavailability (F%) values for octenylsuccinic acid from oral, dermal, and inhalation exposures are 98.7%, 2.12%, and 81.1%, respectively; the predicted C_maxvalues are 5.43, 0.00763, and 3.84 µg/mL respectively. At the dermal exposure level of 100 mg/kg, the predicted C_maxis only 0.753 µg/mL, indicating that at least 500 mg/kg dermal exposure level is required to produce the oral C_maxlevel of 5.43 µg/mL. The predicted human plasma protein binding upon absorption for octenylsuccinic acid is 85.4%. The volume of distribution in humans is estimated to be low (11.2 L, 0.16 L/kg).

Based on the metabolism prediction by ADMET predictor,octenylsuccinic acid will be metabolized to hydroxylated metabolites (by human CYP 2C19). The formed hydroxylated metabolites can also be further metabolized to water soluble metabolites (such as glucuronides and sulfates), which will be mainly excreted into urine and feces.

On the basis of low volume of distribution, and predicted metabolism and excretion,octenylsuccinic acid is not expected to bioaccumulate in humans.