Reaction mass of Disodium decyl(sulphonatophenoxy)benzenesulphonate and Disodium oxybis[decylbenzenesulphonate]

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vitro / ex vivo

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:
Reaction mass of disodium decyl(sulphonatophenoxy)benzenesulphonate and disodium oxybis(decylbenzenesulphonate)
CAS number: 36445-71-3 (Component A) and 70146-13-3 (Component B)
SMILES code:
OS(=O)(=O)c2cc(c(Oc1ccc(cc1)S(=O)(=O)O)cc2)C(C)CCCCCCCC (Component A)
OS(=O)(=O)c2cc(ccc2Oc1ccc(cc1S(=O)(=O)O)C(C)CCCCCCCC)C(C)CCCCCCCC (Component B)

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

Algorithm (OECD Principle 2):
a. Model or submodel name:
For the prediction of Fa%, F%, Cmax, Tmax, and AUC 0-168 of Component A and Component B, a PBPK model was utilized in GastroPlus (version 9) to simulate individual absorption parameters and systemic bioavailability following a single oral (or inhalation or dermal) dose of 1 mg/kg bw in a fed 30-year old human (70 kg). In consideration of the potential applications of this reaction mass, both oral and dermal dose formulation types were defined as a solution in water. 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 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 exposure time were selected based on the US EPA dermal exposure assessment report (US EPA, 1992).
The inhalation dose formulation type was defined to be a powder (aerosol) with a particle size of 2.5 μm mean diameter. This particle size 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 potential for higher risk of adverse 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 inhalation model includes 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 Commission for Radiological Protection Publication 66 (ICRP 66) deposition model described in GastroPlus.
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) based on the structures of Component A and Component B.
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 Component A and Component B were proposed based on the human CYP metabolism scheme 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 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:
i. Component A:
OS(=O)(=O)c2cc(c(Oc1ccc(cc1)S(=O)(=O)O)cc2)C(C)CCCCCCCC
ii. Component B:
OS(=O)(=O)c2cc(c(Oc1ccc(cc1C(C)CCCCCCCC)S(=O)(=O)O)cc2)C(C)CCCCCCCC

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. The major two acid forms (Compound A and Compound B) of Reaction mass of disodium decyl(sulphonatophenoxy)benzenesulphonate and disodium oxybis(decylbenzenesulphonate) 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%, F%, and Cmax of Component A and Component B are predicted by the GastroPlus QSAR program. The plasma protein binding and volume of distribution (Vd) of Component A and Component B are predicted by ADMET Predictor. The potential metabolism and excretion of Component A and Component B 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

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 reaction mass of disodium decyl(sulphonatophenoxy)benzenesulphonate and disodium oxybis(decylbenzenesulphonate) 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:

Reaction mass of Disodium decyl(sulphonatophenoxy)benzenesulphonate and Disodium oxybis[decylbenzenesulphonate]

EC Number:

915-640-4

Molecular formula:

C22 H30 O7 S2 . 2 Na

IUPAC Name:

Reaction mass of Disodium decyl(sulphonatophenoxy)benzenesulphonate and Disodium oxybis[decylbenzenesulphonate]

Test material form:

other: SMILES: OS(=O)(=O)c2cc(c(Oc1ccc(cc1)S(=O)(=O)O)cc2)C(C)CCCCCCCC (Component A) OS(=O)(=O)c2cc(ccc2Oc1ccc(cc1S(=O)(=O)O)C(C)CCCCCCCC)C(C)CCCCCCCC (Component B)

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: 36445-71-3 (Component A) and 70146-13-3 (Component B)
Chemical name: Reaction mass of disodium decyl(sulphonatophenoxy)benzenesulphonate and disodium oxybis(decylbenzenesulphonate)
a. SMILES:
OS(=O)(=O)c2cc(c(Oc1ccc(cc1)S(=O)(=O)O)cc2)C(C)CCCCCCCC (Component A)
OS(=O)(=O)c2cc(ccc2Oc1ccc(cc1S(=O)(=O)O)C(C)CCCCCCCC)C(C)CCCCCCCC (Component B)

Results and discussion

Any other information on results incl. tables

Predicted value (model result):

Absorption:

For Component A at 1 mg/kg exposure dose level in a fed 30-year old human (70 kg) for dermal exposure, the fractional absorption (Fa%) value predicted by GastroPlus is 99.8%; the predicted systemic bioavailability (F%) value is 0.00000715%. The predicted Cmax value is 0.0000000763 μg/mL. While dermal is the relevant route of exposure for component A, at the dermal exposure level of 3.00 mg/kg, the predicted Cmax for Component A is only 0.0000000598 μg/mL, orders of

magnitude below the comparable oral Cmax level of 0.495 μg/mL, indicating lower potential for dermal systemic exposure.

For component B at 1 mg/kg exposure dose level in a fed 30-year old human (70 kg) for dermal exposure, the fractional absorption (Fa%) value predicted by GastroPlus is 98.1%; the predicted systemic bioavailability (F%) value is 0.00000000%. The predicted Cmax value is 0.00000000 μg/mL. While dermal is the relevant route of exposure for component B, the lack of bioavailability by the dermal route indicates that Cmax values will never reach the corresponding level from oral doses. Overall, the dermal bioavailability of Component A is extremely low and there is negligible dermal bioavailability predicted for Component B.

Distribution:

The predicted human plasma protein binding values following absorption for Component A and Component B are 31.0% and 79.0%, respectively. Higher protein binding values generally indicate lower bioavailability to interact with other target sites. The volume of distribution for both Component A and Component B in humans was estimated to be low (0.12 L/kg and 0.15 L/kg, respectively), which indicates low distribution to body tissues.

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%) value of dermal exposure for Component A in humans is 99.8%. The predicted systemic bioavailability (F%) value for Component A from dermal exposure is 0.00000715%. The predicted Cmax value for Component A is 0.0000000763 μg/mL. All of the above predictions were made with GastroPlus v9.0. While dermal is the relevant route of exposure for component A, at the dermal exposure level of 3.00 mg/kg, the predicted Cmax for Component A is only 0.0000000598 μg/mL, orders of magnitude below the comparable oral Cmax level of 0.495 μg/mL, indicating that any dermal exposure level will not produce the oral Cmax level of 0.495 μg/mL due to the extremely low dermal bioavailability of Compound A.
At the same exposure level (1 mg/kg), the predicted fractional absorption (Fa%) value for dermal exposure to Component B by GastroPlus is 98.1%; the predicted systemic bioavailability (F%) value is 0.00000000%. The predicted Cmax value is 0.00000000 μg/mL. While dermal is the relevant route of exposure for component B, the lack of bioavailability by the dermal route indicates that Cmax values will never reach the corresponding level from oral doses.
The low F%, but high Fa% values for dermal exposure for Component A and Component B, are due to the fact that these compounds would mainly be absorbed in the stratum corneum of skin and cannot get into blood circulation in blood. The predicted human plasma protein binding following absorption for
Component A and Component B by any exposure route is 31% and 79%, respectively. The volume of distribution in humans for Component A and Component B was estimated to be 0.12 L/kg and 0.15 L/Kg, respectively, which is relatively low.

Executive summary:

Reaction mass of disodium decyl(sulphonatophenoxy)benzenesulphonate and disodium oxybis(decylbenzenesulphonate) is a UVCB (Unknown or Variable Composition,

Complex Reaction Products and Biological Materials) mixture containing two major components (disodium decyl(sulphonatophenoxy)benzenesulphonate and disodium

oxybis(decylbenzenesulphonate). Experimental data on absorption is not available for this reaction mass. The absorption potential of the reaction mass in humans, based on the corresponding free acid forms of the two major components (Component A and Component B, respectively) of the reaction mass, was estimated utilizing QSAR programs: ADMET predictor (v7.2, Simulations Plus Inc, Lancaster, CA, USA), and GastroPlus (v9.0, Simulations Plus Inc, Lancaster, CA, USA).

At 1 mg/kg exposure dose level in a fed 30-year old human (70 kg), the fractional absorption (Fa%) value for dermal exposure to Component A predicted by GastroPlus is 99.8%. The predicted systemic bioavailability (F%) value is 0.00000715%; the predicted Cmax value is 0.0000000763 μg/mL. At the dermal exposure level of 3 mg/kg, the predicted Cmax for Component A is 0.0000000598 μg/mL, indicating that any dermal exposure level will not produce the oral Cmax level of 0.495 μg/mL. The predicted human plasma protein binding upon absorption for Component A is 31.0%. The volume of distribution in humans is estimated to be low (0.12 L/kg).

At 1 mg/kg exposure dose level in a fed 30-year old human (70 kg), the fractional absorption (Fa%) value for dermal exposure to Component B

predicted by GastroPlus is 98.1%. The predicted systemic bioavailability (F%) value is 0.00000000%, indicating that no dermal absorption was predicted for component B. The predicted Cmax value is 0.00000000 μg/mL. No dermal bioavailability was predicted for Component B, indicating any dermal exposure levels of component B will not produce oral Cmax level of Component B. The predicted human plasma protein binding upon absorption for Component B is 79.0%. The volume of distribution in humans is estimated to be low (0.15 L/kg).