Benzene, 1,1'-oxybis-, tetrapropylene derivs., sulfonated, sodium salts

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Study period:

2016

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:
Major components: monoalkyl diphenyl ether sulfate and dialkyl diphenyl ether sulfate
CAS number: 119345-04-9
SMILES code:
OS(=O)(=O)c2cc(CC(C)C(CCC)C(C)CCC)c(Oc1ccc(cc1)S(=O)(=O)O)cc2 (monoalkyl diphenyl ether sulfate)
OS(=O)(=O)c2cc(CC(C)C(CCC)C(C)CCC)c(Oc1ccc(cc1CC(C)C(CCC)C(C)CCC)S(=O)(=O)O)cc2 (dialkyl diphenyl ether sulfate)

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
Endpoint (OECD Principle 1)
i. The absorption fraction (Fa%) of the major monoalkyl and dialkyl diphenyl ether sulfate components of DOWFAX 2A1 following 90-day repeated oral and dermal exposures in humans.

ii. Systemic bioavailability (F%) of the major monoalkyl and dialkyl diphenyl ether sulfate components of DOWFAX 2A1 following 90-day repeated oral and dermal exposures in humans.

iii. The plasma protein binding and volume of distribution (Vd) of the major monoalkyl and dialkyl diphenyl ether sulfate components of DOWFAX 2A1.

iv. The potential metabolism and excretion of the major monoalkyl and dialkyl diphenyl ether sulfate components of DOWFAX 2A1 in human.

Algorithm (OECD Principle 2):
a. Model or submodel name:
For the prediction of Fa%, F%, and AUC 2160 of the major monoalkyl and dialkyl diphenyl ether sulfate components of DOWFAX 2A1, a PBPK model was utilized in GastroPlus (version 9) to simulate absorption parameters and systemic bioavailability of the major monoalkyl and dialkyl diphenyl ether sulfate components of DOWFAX 2A1 following 90-day repeated exposure at an oral dose level of 9 mg/kg/day or dermal exposure level of 90 mg/kg/day 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. 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 dose formulation type was defined to be a liquid suspension with particle size of 50 µM mean diameter. 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 10 cm2 on human arm with dose volume of 10 mL.

Bioavailability predictions for these two exposure routes were made by including metabolism of the major five major cytochrome (CYP) P450 enzymes (1A2, 2C9, 2C19, 2D6, and 3A4) in human in the PBPK simulations. 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 structures of the major monoalkyl and dialkyl diphenyl ether sulfate components of DOWFAX 2A1. The plasma protein binding and volume distribution (Vd) were predicted by ADMET Predictor (v7.5, Simulations Plus Inc, Lancaster, CA, USA).

The metabolism and excretion of the major monoalkyl and dialkyl diphenyl ether sulfate components of DOWFAX 2A1 were 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(TM) (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 modeling 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. OS(=O)(=O)c2cc(CC(C)C(CCC)C(C)CCC)c(Oc1ccc(cc1)S(=O)(=O)O)cc2 (monoalkyl diphenyl ether sulfate)
ii. OS(=O)(=O)c2cc(CC(C)C(CCC)C(C)CCC)c(Oc1ccc(cc1CC(C)C(CCC)C(C)CCC)S(=O)(=O)O)cc2 (dialkyl diphenyl ether sulfate)

5. APPLICABILITY DOMAIN:
Descriptor values: Applicability domain (OECD principle 3)
a. 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 to certain degree the size and complexity of input molecules to no more than 256 bonds and no more than 20 ionizable groups.
ii. Structural fragment domain: ADMET Predictor and GastroPlus use calculated descriptors for each structure as inputs to its predictive models, not structural fragments
iii. Mechanism domain: ADMET Predictor and GastroPlus models use QSAR/QSPR methodology, which is a subset of statistical-correlative modelling. It does not consider mechanisms of
action.
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 chemicals risk assessment.
Approach for regulatory interpretation of the model result: The 90-day repeated oral and dermal exposure Fa%, F%, and AUC0-2160 of the major monoalkyl and dialkyl diphenyl ether sulfate components of DOWFAX 2A1 were predicted by GastroPlus QSAR program. The plasma protein binding and volume distribution (Vd) of the major monoalkyl and dialkyl diphenyl ether sulfate components of DOWFAX 2A1 were predicted by ADMET Predictor. The potential metabolism and excretion of the major monoalkyl and dialkyl diphenyl ether sulfate components were proposed according to human CYP metabolism predicted by ADMET Predictor.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

To assess the ADME potential of the major monoalkyl and dialkyl diphenyl ether sulfate components of DOWFAX 2A1 in humans, the QSAR programs, ADMET predictor (v7.2, Simulations Plus Inc, Lancaster, CA, USA) and Gastro Plus (v9.0, Simulations Plus Inc, Lancaster, CA, USA) were used.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Benzene, 1,1'-oxybis-, tetrapropylene derivs., sulfonated, sodium salts

EC Number:

601-601-6

Cas Number:

119345-04-9

Molecular formula:

C24H32O7S2Na2

IUPAC Name:

Benzene, 1,1'-oxybis-, tetrapropylene derivs., sulfonated, sodium salts

Details on test material:

Major components: monoalkyl and dialkyl diphenyl ether sulfate

Specific details on test material used for the study:

CAS number: 119345-04-9
EC number: 601-601-6
Chemical name: DOWFAX 2A1 (Benzene, 1,1'-oxybis-, tetrapropylene derivs., sulfonated, sodium salts)
SMILES:
OS(=O)(=O)c2cc(CC(C)C(CCC)C(C)CCC)c(Oc1ccc(cc1)S(=O)(=O)O)cc2 (monoalkyl diphenyl ether sulfate)
OS(=O)(=O)c2cc(CC(C)C(CCC)C(C)CCC)c(Oc1ccc(cc1CC(C)C(CCC)C(C)CCC)S(=O)(=O)O)cc2 (dialkyl diphenyl ether sulfate)

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

The predicted oral and dermal values for monoalkyl diphenyl ether sulfate and dialkyl diphenyl ether sulfate respectively: Fa% 94.8%, 25.7%, and 0.16%, 0.003%, F% 54.1%, 14.9% and 0.00%, 0.00%, AUC 0-2160 µg h/mL 11780, 30820 and 0.00%, 0.00%

Main ADME results 2

Type:

distribution

Results:

Predicted human plasma protein binding values following absorption for monoalkyl diphenyl ether sulfate and dialkyl diphenyl ether sulfate are 43% and 80% respectively. The volume of distribution values were estimated to be low (0.13L/Kg and 0.15L/Kg).

Main ADME results 3

Type:

metabolism

Results:

Metabolism prediction: Monoalkyl diphenyl ether sulfate and dialkyl diphenyl ether sulfate will be metabolized to hydroxylated metabolites and can be further metabolized to water soluble metabolites which will be mainly excreted into urine and feces.

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 compounds; therefore, these metabolites would be expected to be excreted in urine and feces.

Main ADME results 5

Type:

other: Accumulation

Results:

On the basis of low volume of distribution and predicted metabolism and excretion, DOWFAX 2A1 is not expected to bioaccumulate in humans.

Any other information on results incl. tables

Predicted value (model result):

Absorption:

The predicted oral fractional absorption (Fa%) values for the major monoalkyl and dialkyl diphenyl ether sulfate components of DOWFAX 2A1 in human by GastroPlus are 94.8% and 25.7%, respectively. The predicted dermal fractional absorption (Fa%) values for the major monoalkyl and dialkyl diphenyl ether sulfate components of DOWFAX 2A1 in human by GastroPlus are 0.16% and 0.003%, respectively. CYP based metabolism is predicted for the major monoalkyl and dialkyl diphenyl ether sulfate components of DOWFAX 2A1, with the oral systemic bioavailability (F%) predicted to be 54.1% and 14.9%, respectively, and the dermal systemic bioavailability (F%) predicted to be 0.00% and 0.00%, respectively.

Distribution:

The predicted human plasma protein binding values upon absorption for the major monoalkyl and dialkyl diphenyl ether sulfate components of DOWFAX 2A1 are 43% and 80%, respectively. The volume of distribution values in human are estimated to be low (0.13 and 0.15 L/Kg, respectively).

Accumulation:

On the basis of low volume of distribution, the major monoalkyl and dialkyl diphenyl ether sulfate components of DOWFAX 2A1 are not expected to bioaccumulate. Thus DOWFAX 2A1 will not have bioaccumulative potential in humans.

Metabolism:

Based on the metabolism prediction by ADMET predictor, the major monoalkyl and dialkyl diphenyl ether sulfate components of DOWFAX 2A1 will be metabolized to the hydroxylated metabolites (by human CYP enzymes). 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 compounds; therefore, they would be expected to be excreted in urine and feces.

Applicant's summary and conclusion

Conclusions:

Based on the 90-day repeated exposure scenario at the dose level of 9 mg/kg/day, the predicted oral fractional absorption (Fa%), CYP based metabolism related bioavailability (%), and AUC(0-2160), (area under curve, µg h/mL) values for the most abundant DOWFAX 2A1 component (monoalkyl diphenyl ether sulfate) in humans were 94.8%, 54.1%, and 11780, respectively. In the same exposure scenario, the predicted oral fractional absorption (Fa%), CYP based metabolism related bioavailability (%), and AUC0_2160 (area under curve, µg h/mL) value for the dialkyl diphenyl ether sulfate component in humans were 25.7%, 14.9%, and 30820, respectively.

Based on 90-day repeated exposure scenario at the dose level of 90 mg/kg/day, the predicted dermal fractional absorption (Fa%), CYP based metabolism related bioavailability (%), and AUC(0-2160), (area under curve, µg h/mL) values for the monoalkyl diphenyl ether sulfate component in humans were 0.16%, 0.00%, and 0.00%, respectively. In the same exposure scenario, the predicted dermal fractional absorption (Fa%), CYP based metabolism related bioavailability (%), and AUC(0-2160), (area under curve, µg h/mL) values for the dialkyl diphenyl ether sulfate component in humans by GastroPlus were 0.003%, 0.00%, and 0.00%, respectively.

The predicted human plasma protein binding values upon absorption for the monoalkyl diphenyl ether sulfate and dialkyl diphenyl ether sulfate are 43% and 80%, respectively. The volume of distribution values in humans for the monoalkyl diphenyl ether sulfate and dialkyl diphenyl ether sulfate are estimated to be low (0.13 L/kg and 0.15 L/Kg, respectively).

Based on the metabolism prediction by ADMET predictor, the monoalkyl diphenyl ether sulfate and dialkyl diphenyl ether sulfate components of DOWFAX 2A1 will be metabolized to the hydroxylated metabolites (by human CYP enzymes). The formed hydroxylated metabolites can 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 of the monoalkyl diphenyl ether sulfate and dialkyl diphenyl ether sulfate, DOWFAX 2A1 is not expected to bioaccumulate in humans.

Executive summary:

Experimental data on absorption, distribution, metabolism and excretion (ADME) are not available for DOWFAX 2A1 surfactant. To assess the ADME potential of the major monoalkyl and dialkyl diphenyl ether sulfate components of DOWFAX 2A1 in humans, the QSAR programs, ADMET predictor (v7.2, Simulations Plus Inc, Lancaster, CA, USA) and Gastro Plus (v9.0, Simulations Plus Inc, Lancaster, CA, USA) were used.

Based on a 90-day repeated exposure scenario at the dose level of 9 mg/kg/day, the predicted oral fractional absorption (Fa%), CYP based metabolism related bioavailability (%), and AUC_0-2160, (area under curve, µg h/mL) values for the most abundant monoalkyl diphenyl ether sulfate DOWFAX 2A1 component in humans were 94.8%, 54.1%, and 11780, respectively. In the same exposure scenario, the predicted oral fractional absorption (Fa%), CYP based metabolism related bioavailability (%), and AUC_0-2160 (area under curve, µg h/mL) values for the dialkyl diphenyl ether sulfate component in humans were 25.7%, 14.9%, and 30820, respectively.

Based on a 90-day repeated exposure scenario at the dose level of 90 mg/kg/day, the predicted dermal fractional absorption (Fa%), CYP based metabolism related bioavailability (%), and AUC_0-2160 (area under curve, µg h/mL) values for the monoalkyl diphenyl ether sulfate component in humans were 0.16%, 0.00%, and 0.00%, respectively. In the same exposure scenario, the predicted dermal fractional absorption (Fa%), CYP based metabolism related bioavailability (%), and AUC₀_₂₁₆₀ (area under curve, µg h/mL) values for the dialkyl diphenyl ether sulfate component in humans were 0.003%, 0.00%, and 0.00%, respectively.

The predicted human plasma protein binding values upon absorption for monoalkyl diphenyl ether sulfate and dialkyl diphenyl ether sulfate were 43% and 80%, respectively. The volume of distribution values in humans for monoalkyl diphenyl ether sulfate and dialkyl diphenyl ether sulfate were estimated to be low (0.13 L/kg and 0.15 L/Kg, respectively).

Based on the metabolism prediction by ADMET predictor, both monoalkyl diphenyl ether sulfate and dialkyl diphenyl ether sulfate will be metabolized on their alkyl chain to the hydroxylated metabolites (by human CYP enzymes). The formed hydroxylated metabolites can 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, DOWFAX 2A1 is not expected to bioaccumulate in humans.