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. 2021 Jul;51(7):831-841.
doi: 10.1080/00498254.2021.1927239. Epub 2021 May 24.

Phenolic benzotriazoles: a class comparison of toxicokinetics of ultraviolet-light absorbers in male rats

Suramya Waidyanatha  1 , Esra Mutlu  1 , Seth Gibbs  2 , Jessica Pierfelice  2 , Jeremy P Smith  2 , Brian Burback  2 , Chad T Blystone  1
Affiliations

Phenolic benzotriazoles: a class comparison of toxicokinetics of ultraviolet-light absorbers in male rats

Suramya Waidyanatha et al. Xenobiotica. 2021 Jul.

Abstract

Phenolic benzotriazoles are ultraviolet-light absorbers used in a variety of industrial and consumer applications. We investigated the toxicokinetic behaviour of 9 compounds, covering unsubstituted, monosubstituted, disubstituted, and trisubstituted compounds, following a single gavage (30 and 300 mg/kg) and intravenous (IV) (2.25 mg/kg) administration in male rats.Following IV administration, no distinct pattern in plasma elimination was observed for the compounds with half-lives ranging from 15.4-84.8 h. Systemic exposure parameters, maximum concentration (Cmax) and area under the concentration time curve (AUC), generally increased with the degree of substitution.Following gavage administration, Cmax and AUC of unsubstituted compound were lower compared to the substituted compounds. Cmax and AUC increased ≤7-fold with a 10-fold increase in the dose except for the AUC of the unsubstituted compound where the increase was 30-fold. Plasma elimination half-lives for the class ranged from 1.57 to 192 h with the exception of 30 mg/kg drometrizole.Oral bioavailability was low with ∼ 6% estimated for unsubstituted compound and 12.8-23% for others at 30 mg/kg dose. Bioavailability was lower following administration of the higher dose.Taken collectively, these data point to low oral absorption of phenolic benzotriazoles. The absorption decreased with increasing dose. Substituted compounds may be less metabolized compared to the unsubstituted.

Keywords: Phenolic benzotriazoles; elimination half-life; rats; systemic exposure.

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Figures

Figure 1.
Figure 1.
Structures of phenolic benzotriazoles
Figure 2.
Figure 2.
Plasma concentration versus time profiles following a single intravenous administration of 2.25 mg/kg phenolic benzotriazoles in male rats. A) unsubstituted B) monosubstituted C) disubstitued D) trisubstituted. Lines shown are for model fits based on a three-compartmental model with bolus Input and first order output and 1/Y^2 weighting (model 18). P-BZT, 2-(2H-Benzotriazol-2-yl)phenol; tBu-BZT, 2-(2H-Benzotriazol-2-yl)-4-tertbutylphenol; ditPe-BZT, 2-(2H-Benzotriazol-2-yl)-4,6- bis(1,1-dimethylpropyl)phenol; diMeEtPh-BZT, 2-(2H-Benzotriazol-2-yl)-4,6-bis(1-methyl-1-phenylethyl)phenol; tBuPrOcEst-BZT, 3-(2H-Benzotriazol-2-yl)-5-(1,1-dimethylethyl)-4-hydroxybenzenepropanoic acid, octyl ester; ditBuCl-BZT, 2-(5-Chloro-2H-benzotriazol-2-yl)-4,6-bis(1,1dimethylethyl)phenol. For tBuPrOcEst-BZT, data for the corresponding acid, 3-(2H-benzotriazol-2-yl)-5(1,1-dimethylethyl)-4-hydrobenzenepropanoic acid (tBuPrA-BZT) is shown.
Figure 2.
Figure 2.
Plasma concentration versus time profiles following a single intravenous administration of 2.25 mg/kg phenolic benzotriazoles in male rats. A) unsubstituted B) monosubstituted C) disubstitued D) trisubstituted. Lines shown are for model fits based on a three-compartmental model with bolus Input and first order output and 1/Y^2 weighting (model 18). P-BZT, 2-(2H-Benzotriazol-2-yl)phenol; tBu-BZT, 2-(2H-Benzotriazol-2-yl)-4-tertbutylphenol; ditPe-BZT, 2-(2H-Benzotriazol-2-yl)-4,6- bis(1,1-dimethylpropyl)phenol; diMeEtPh-BZT, 2-(2H-Benzotriazol-2-yl)-4,6-bis(1-methyl-1-phenylethyl)phenol; tBuPrOcEst-BZT, 3-(2H-Benzotriazol-2-yl)-5-(1,1-dimethylethyl)-4-hydroxybenzenepropanoic acid, octyl ester; ditBuCl-BZT, 2-(5-Chloro-2H-benzotriazol-2-yl)-4,6-bis(1,1dimethylethyl)phenol. For tBuPrOcEst-BZT, data for the corresponding acid, 3-(2H-benzotriazol-2-yl)-5(1,1-dimethylethyl)-4-hydrobenzenepropanoic acid (tBuPrA-BZT) is shown.
Figure 3.
Figure 3.
Plasma concentration versus time profiles following a single gavage administration of 300 mg/kg phenolic benzotriazoles in male rats. A) unsubstituted B) monosubstituted C) disubstitued D) trisubstituted. Lines shown are for model fits based on a two-compartmental model with first order Input and first order output and 1/Y^2 weighting (model 13). P-BZT, 2-(2H-Benzotriazol-2-yl)phenol; tBu-BZT, 2-(2H-Benzotriazol-2-yl)-4-tertbutylphenol; ditPe-BZT, 2-(2H-Benzotriazol-2-yl)-4,6- bis(1,1-dimethylpropyl)phenol; diMeEtPh-BZT, 2-(2H-Benzotriazol-2-yl)-4,6-bis(1-methyl-1-phenylethyl)phenol; tBuPrOcEst-BZT, 3-(2H-Benzotriazol-2-yl)-5-(1,1-dimethylethyl)-4-hydroxybenzenepropanoic acid, octyl ester; ditBuCl-BZT, 2-(5-Chloro-2H-benzotriazol-2-yl)-4,6-bis(1,1dimethylethyl)phenol. For tBuPrOcEst-BZT, data for the corresponding acid is shown.
Figure 3.
Figure 3.
Plasma concentration versus time profiles following a single gavage administration of 300 mg/kg phenolic benzotriazoles in male rats. A) unsubstituted B) monosubstituted C) disubstitued D) trisubstituted. Lines shown are for model fits based on a two-compartmental model with first order Input and first order output and 1/Y^2 weighting (model 13). P-BZT, 2-(2H-Benzotriazol-2-yl)phenol; tBu-BZT, 2-(2H-Benzotriazol-2-yl)-4-tertbutylphenol; ditPe-BZT, 2-(2H-Benzotriazol-2-yl)-4,6- bis(1,1-dimethylpropyl)phenol; diMeEtPh-BZT, 2-(2H-Benzotriazol-2-yl)-4,6-bis(1-methyl-1-phenylethyl)phenol; tBuPrOcEst-BZT, 3-(2H-Benzotriazol-2-yl)-5-(1,1-dimethylethyl)-4-hydroxybenzenepropanoic acid, octyl ester; ditBuCl-BZT, 2-(5-Chloro-2H-benzotriazol-2-yl)-4,6-bis(1,1dimethylethyl)phenol. For tBuPrOcEst-BZT, data for the corresponding acid is shown.
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