4-(4-nitrophenylazo)-2,6-di-sec-butyl-phenol

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

2014

Reliability:

2 (reliable with restrictions)

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

GLP compliance:

no

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
On the basis of low oral and inhalation bioavailability, low volume of distribution, and predicted metabolism and excretion, 4-(4-nitrophenylazo)-2,6-di-sec-butylphenol is not expected to bioaccumulate.

Executive summary:

Experimental data on absorption, distribution, metabolism and excretion (ADME) are not available for 4-(4-nitrophenylazo)-2,6-di-sec-butylphenol. To assess the ADME potential of 4-(4-nitrophenylazo)-2,6-di-sec-butylphenol in human, the QSAR programs. ADMET predictor, Gastro Plus (v8.5, Simulations Plus Inc, Lancaster, CA, USA), and EPI Suite (version 4.1., USEPA, USA), were used. Additionally, published literature on metabolism of some analogs (Azo dyes) of 4-(4-Nitrophenylazo)-2,6-di-sec-butylphenol were also used. The predicted fractional absorption (Fa%) values of oral and inhalation for 4-(4- nitrophenylazo)-2,6-di-sec-butylphenol in human by GastroPlus are 0.59% and 0.48%, respectively.

As 4-(4-Nitrophenylazo)-2,6-di-sec-butylphenol can be metabolized to 4-amino-2,6-di-sec-butylphenol and 4-nitroaniline in human intestine, these two metabolites were further evaluated for fraction absorption (Fa%) and bioavailability(F%) from both dermal and oral exposure routes via GastroPlus. The predicted oral Fa% for 4-amino-2,6-di-sec-butylphenol and 4-nitroaniline were 99.8% and 100%, respectively; The predicted dermal Fa% for 4-amino-2,6-di-sec-butylphenol and 4-nitroaniline were 99.7% and 97.1%, respectively; The predicted oral F% for 4-amino-2,6-di-sec-butylphenol and 4-nitroaniline were 97.9% and 97.4%, respectively; The predicted dermal F% for 4-amino-2,6-di-sec-butylphenol and 4-nitroaniline were 97.9% and 78.1%, respectively.

CYP based metabolism is predicted for 4-(4-nitrophenylazo)-2,6-di-secbutylphenol with the systemic bioavailability (F%) of both oral absorption and inhalation predicted to be 0.37% and 0.29% for 4-(4-nitrophenylazo)-2,6-di-sec-butylphenol, respectively. The dermal permeability coefficient (Kp), the dermally absorbed dose per event (DAevent), and Dermal Absorbed Dose (DAD) for 4-(4-nitrophenylazo)-2,6-di-secbutylphenol were predicted as 0.793 cm/hr, 4 .0x10-5 mg/cm²-event (duration 10.5 h, time to reach steady state 46.4 h), 4.23 μg/kg-day (70 kg adult, water contact), respectively. The predicted human plasma protein binding upon absorption for 4-(4-nitrophenylazo)-2,6- di-sec-butylphenol is 98.7%. The volume of tissue distribution in humans was estimated to be low (2.33 L/kg). Based on the metabolism information of related Azo dyes, 4-(4-nitrophenylazo)-2,6-di-secbutylphenol will be metabolized to the hydroxylated metabolites (by CYP enzymes) and the corresponding phenolic compound and nitroaliline (by Azo reduction). The formed metabolites (and parent compound) can also be further metabolized water soluble metabolites (such as glucuronides and sulfates), which will be mainly excreted into urine and feces. On the basis of low oral and inhalation bioavailability, low volume of distribution, and predicted metabolism and excretion, 4-(4-nitrophenylazo)-2,6-di-sec-butylphenol is not expected to bioaccumulate.

Description of key information

QSAR assessment of bioavailability, metabolism and bioaccumulation potential

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

1

Absorption rate - dermal (%):

1

Absorption rate - inhalation (%):

1

Additional information

Experimental data on absorption, distribution, metabolism and excretion (ADME) are not available for 4-(4-nitrophenylazo)-2,6-di-sec-butylphenol. To assess the ADME potential of 4-(4-nitrophenylazo)-2,6-di-sec-butylphenol in human, the QSAR programs. ADMET predictor, Gastro Plus (v8.5, Simulations Plus Inc, Lancaster, CA, USA), and EPI Suite (version 4.1., USEPA, USA), were used. Additionally, published literature on metabolism of some analogs (Azo dyes) of 4-(4-Nitrophenylazo)-2,6-di-sec-butylphenol were also used.

Absorption:

The predicted fractional absorption (Fa%) values of oral and inhalation for 4-(4- nitrophenylazo)-2,6-di-sec-butylphenol in human by GastroPlus are 0.59% and 0.48%, respectively. CYP based metabolism is predicted for 4-(4-nitrophenylazo)-2,6-di-secbutylphenol with the systemic bioavailability (F%) of both oral absorption and inhalation predicted to be 0.37% and 0.29% for 4-(4-nitrophenylazo)-2,6-di-sec-butylphenol, respectively. The dermal permeability coefficient (Kp), the dermally absorbed dose per event (DAevent), and Dermal Absorbed Dose (DAD) for 4-(4-nitrophenylazo)-2,6-di-secbutylphenol were predicted as 0.793 cm/hr, 4 .0x10-5 mg/cm²-event (duration 10.5 h, time to reach steady state 46.4 h), 4.23 μg/kg-day (70 kg adult, water contact), respectively.

4-(4-Nitrophenylazo)-2,6-di-sec-butylphenol can be metabolized to 4-amino-2,6-di-sec-butylphenol and 4-nitroaniline in human intestine and to a much lesser extent on the human skin. Consequently these two metabolites were further evaluated for fraction absorption (Fa%) and bioavailability (F%) from both dermal and oral exposure routes via GastroPlus. The predicted oral Fa% for 4-amino-2,6-di-sec-butylphenol and 4-nitroaniline were 99.8% and 100%, respectively; The predicted dermal Fa% for 4-amino-2,6-di-sec-butylphenol and 4-nitroaniline were 99.7% and 97.1%, respectively. The predicted oral F% for 4-amino-2,6-di-sec-butylphenol and 4-nitroaniline were 97.9% and 97.4%, respectively. The predicted dermal F% for 4-amino-2,6-di-sec-butylphenol and 4-nitroaniline were 97.9% and 78.1%, respectively.

In summary, prior to metabolism of the azo bond in this compound, the bioavailability via oral, inhalation and dermal routes is predicted to be very low. However once the azo bond has been reduced (either in the gut or to a lesser extent on the skin) the metabolites will be almost completely absorbed via both oral and dermal routes. Azo reduction is not known to occur in the lungs and respiratory tract due to the reliance on bacteria for this metabolic pathway to occur ex-vivo. Consequently, when comparing toxicity via the oral route to the inhalation route it must be understood that the bioavailability of parent compound and metabolites will be substantially lower than via the oral route, and toxicity would be expected to be substantially lower.

Distribution, metabolism and excretion:

The predicted human plasma protein binding upon absorption for 4-(4-nitrophenylazo)-2,6- di-sec-butylphenol is 98.7%. The volume of tissue distribution in humans was estimated to be low (2.33 L/kg). Based on the metabolism information of related Azo dyes, 4-(4-nitrophenylazo)-2,6-di-secbutylphenol will be metabolized to the hydroxylated metabolites (by CYP enzymes) and the corresponding phenolic compound and nitroaliline (by Azo reduction). The formed metabolites (and parent compound) can also be further metabolized water soluble metabolites (such as glucuronides and sulfates), which will be mainly excreted into urine and feces.

Bioaccumulation potential:

On the basis of low oral and inhalation bioavailability, low volume of distribution, and predicted metabolism and excretion, 4-(4-nitrophenylazo)-2,6-di-sec-butylphenol is not expected to bioaccumulate.