Metabolism of ortho-, meta-, and para-toluidine in the adult male rat

Cheever, Kenneth L.; Richards, Donald E.; Plotnick, Harry B.

doi:10.1016/0041-008x(80)90069-1

Cited by 32 publications

(19 citation statements)

References 14 publications

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“…The expected similar range of metabolism and carcinogenic effect is supported by the experimental carcinogenicity. The predicted ring p-hydroxylation is in agreement with the experimental data [56].…”

Section: Docking Resultssupporting

confidence: 82%

“…As in the case of rat CYP2E1 aniline complex, the LBE values for ortho and para positions were similar, and there was a significant ortho energy contribution. This can explain the experimentally equal range of para and ortho metabolites [56] and the higher carcinogenicity in rat than in mouse. The distance to the Fe atom and LBE values of mouse enzyme were respectively 1.85 Å and À0.97 kcal/mol, which are close to the aniline values for mouse.…”

Section: Docking Resultsmentioning

confidence: 87%

“…4-Chloro-o-toluidine and N,N 0 -dimethylaniline undergo CYP2 metabolism [53][54][55]. For the remaining chemicals experimental data about P450 metabolism was not available, but general metabolic pathways and products for m-toluidine and o-toluidine are known [56]. The chemical structure of these compounds [37,38] lead to the assumption about CYP2E1 metabolism that is discussed below.…”

Section: Docking Resultsmentioning

confidence: 99%

See 2 more Smart Citations

A combination of 3D-QSAR, docking, local-binding energy (LBE) and GRID study of the species differences in the carcinogenicity of benzene derivatives chemicals

Fratev

Benfenati

2008

Journal of Molecular Graphics and Modelling

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Section: Docking Resultssupporting

confidence: 82%

Section: Docking Resultsmentioning

confidence: 87%

Section: Docking Resultsmentioning

confidence: 99%

See 1 more Smart Citation

A combination of 3D-QSAR, docking, local-binding energy (LBE) and GRID study of the species differences in the carcinogenicity of benzene derivatives chemicals

Fratev

Benfenati

2008

Journal of Molecular Graphics and Modelling

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“…The main metabolite is 4-amino-3-methylphenol (synonym 4-amino-m-cresol) and small amounts of the N-hydroxy-derivative are also formed (Son et al, 1980;Kulkarni et al, 1983). Unmetabolized o-toluidine is also excreted in the urine of rats at concentrations that are high (21-36%) in comparison to the noncarcinogenic p-and m-toluidine isomers (2.5% each), and contact of the parent compound with the urinary bladder was proposed as a basis for o-toluidine tumorigenesis in this organ (Cheever et al, 1980). A physiologically based pharmacokinetic model to permit quantitative comparisons between rats and humans, however, is not available.…”

Section: Introductionmentioning

confidence: 96%

“…Radiotracer studies in rats show the oral bioavailability is high, and tissue distribution is widespread. Approximately 92% of the dose was recovered in the urine within 24 h of a 50 mg/kg gavage dose (Cheever et al, 1980;Brock et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Establishing a total allowable concentration of o-toluidine in drinking water incorporating early lifestage exposure and susceptibility

English

Bhat

Ball

et al. 2012

Regulatory Toxicology and Pharmacology

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o-Toluidine is a monocyclic aromatic amine present in the formulation of some materials that contact drinking water. NSF/ANSI 61 Annex A (2011) and US EPA (2005a) risk assessment guidelines were used to determine an acceptable drinking water level. Occupational exposure to o-toluidine is associated with an increased risk of bladder cancer but human disease rates could not be used to establish risk values due to inadequate exposure data and coexposures in the epidemiology cohorts. Chronic dietary exposure to o-toluidine hydrochloride was associated with benign and malignant tumors in both sexes of F344 rats and B6C3F1 mice. o-Toluidine is genotoxic in vitro and in vivo. A 10(-5) cancer risk level was extrapolated from the human equivalent BMDL(10) of 13mg/kg-day for the combined incidence of papillomas and carcinomas of the bladder transitional epithelium in female rats. Considering varying susceptibility to tumor development at different life stages, the unit risk was modified to incorporate potency adjustments for early-life exposures. A framework for lifestage adjustment is presented that makes assumptions evident. For this assessment, the lifetime unit risk derived was ∼2-fold greater than the unadjusted adult lifetime unit risk, and the resulting Total Allowable Concentration in drinking water is 20μg/L.

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Biological monitoring of o-toluidine in urine pretreated by an enzymatic deconjugation method

Eitaki

Nakano

Kawai³

et al. 2019

Journal of Occupational Health

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Objectives To establish an enzymatic deconjugation method to separately quantify urinary o‐toluidine (OT), its six metabolites, another six chemicals present in an OT‐processing plant, and one metabolite of p‐toluidine, and to propose optimal urinary biological monitoring items of OT exposure. Methods Thirty‐six urine samples of an OT‐processing plant's workers were obtained and pretreated by an enzymatic deconjugation method employing β‐glucuronidase/arylsulfatase for 3 hours at 37°C and measured by liquid chromatograph‐mass spectrometry (LC‐MS). An alkaline hydrolytic pretreatment and 1‐chlorobutane extraction procedure was also examined as a widely used urinary OT measurement method. Results The 14 chemicals were separated by LC‐MS condition set by us and 13 chemicals other than 2‐chloroaniline showed satisfiable linearity and limits of determination. Standard substances of six OT metabolites decomposed after the alkaline heating. In the 36 urine samples, OT, N‐(4‐hydroxy‐2‐methylphenyl) acetamide (NHM), and 4‐amino‐m‐cresol (ACR) accounted for approx. 90% of the total OT and OT metabolites, but inter‐individual variation of the three substance excretion seemed to be wide. Time course of urinary excretion revealed that concentration of the three substances was higher 24 hours after the work shift's end rather than just after the work shift. Conclusions OT and its six metabolites can each be determined with LC‐MS. The alkaline method is not so optimal for exact biological monitoring. Rather, the sum of urinary OT, NHM, and ACR measured by the enzymatic method is a better index, and "end of the workweek" is a good urine‐sampling time for the biological monitoring of OT exposure.

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Metabolism of ortho-, meta-, and para-toluidine in the adult male rat

Cited by 32 publications

References 14 publications

A combination of 3D-QSAR, docking, local-binding energy (LBE) and GRID study of the species differences in the carcinogenicity of benzene derivatives chemicals

A combination of 3D-QSAR, docking, local-binding energy (LBE) and GRID study of the species differences in the carcinogenicity of benzene derivatives chemicals

Establishing a total allowable concentration of o-toluidine in drinking water incorporating early lifestage exposure and susceptibility

Biological monitoring of o-toluidine in urine pretreated by an enzymatic deconjugation method

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