Dinitrotoluene

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Reliabiliy as cited in OECD SIDS Dinitrotoluene (isomers mixture) CAS No.: 25321-14-6, 2004. Meets generally accepted scientific standards, limited documentation and acceptable for assessment

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Identification and Quantification of Urinary Metabolites of Dinitrotoluenes in Occupationally Exposed Humans

Author:

Turner, M.J. Jr et al.

Year:

1985

Bibliographic source:

Toxicology and Pharmacology 80, 166-174

Reference 2

Reference Type:

publication

Title:

Assessing Exposure to Dinitrotoluene Using a Biological Monitoring

Author:

Levine, R.J. et al.

Year:

1985

Bibliographic source:

Journal of Occupational Medicine 27(9), 627-638

Reference 3

Reference Type:

secondary source

Title:

Dinitrotoluene (isomers mixture), CAS No.: 25321-14-6

Author:

OECD SIDS

Year:

2004

Materials and methods

Objective of study:

other: metabolism and excretion

Principles of method if other than guideline:

Exposure of workers to dinitrotoluene (DNT) was evaluated at a DNT manufactoring plant by collecting the urine over a 72 h period and analyzing it for 2,4 and 2,6-DNT and putative metabolites by gas chromatography-mass-spectrometry.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Dinitrotoluene

EC Number:

246-836-1

EC Name:

Dinitrotoluene

Cas Number:

25321-14-6

Molecular formula:

C7H6N2O4

IUPAC Name:

Reaction mass of 1-methyl-2,4-dinitrobenzene and 2-methyl-1,3-dinitrobenzene

Details on test material:

- Name of test material (as cited in study report): Dinitrotoluene (DNT), technical grade
- Analytical purity: 76.4% 2,4-DNT, 18.8% 2,6-DNT and 4.8% other isomers

Radiolabelling:

no

Test animals

Species:

human

Sex:

male/female

Administration / exposure

Route of administration:

inhalation

Vehicle:

other: air

Details on exposure:

Inhalation exposure:
7 h personal air samples were taken from the breathing zone of several persons using a stainless steel tube (packed with Tenax GC), connected to a small vacuum pump and flow meter. Air flow through the sampling tube was set at 50 mL/min. The quantity of 2,4 and 2,6-DNT in the sampling tube was analyzed by gas chromatography/mass spectrometry. Lower detection limit was approx. 0.1 µg of each DNT isomer per sample.
Overall 11 samples were taken from the breathing zone of 5 employees with 4 different job titles.

Dermal exposure:
Absorption was measured by quantification of excreted DNT metabolites in the urine.

Duration and frequency of treatment / exposure:

72 h period including three work shifts

Doses / concentrations

Remarks:

Doses / Concentrations:
Estimated 2,4-DNT in air inhaled during the work shift: 0.1 - 4.3 mg/10m3
Estimated 2,4 and 2,6-DNT in air inhaled during the work shift: 0.5 - 5.9 mg/10m3

No. of animals per sex per dose / concentration:

17 employees (14 men, 4 women): 13 day shift-workers and 4 office employees
3 researchers

Details on study design:

3 researchers were involved for collecting and processing urine samples, reviewing work diaries, and taking air samples.
A detailed description of the DNT manufactoring process and the different jobs for the 17 employees were given.

Details on dosing and sampling:

Collection of urine:
Each voiding was collected in separate polypropylene cubs. Participants were required to void at the beginning and end of each workshift. Samples obtained during the workshifts were collected during rounds of the plants (every 2 h) or at the conclusion of the shift. Urines collected during non-working hours were brought to the plant the following morning. After the total volume has been measured, an aliquot of each sample was frozen immediately until analysis. Analysis for 2,4-and 2,6-DNT and metabolites was performed by gas chromatography/mass spectrometry (detection limit of each isomer: 0.1 µg/mL per)

Collection and analyzing of surface wipe samples:
After conclusion of the 72h monitoring period, wipe specimens were obtained from the skin (hands and foreheads) of DNT workers not involved in the urine collection and from surfaces of objects in the work area that might contact the skin. Areas suspected of DNT contamination were wiped with cotton gauze pad soaked in 98% isopropyl alcohol. The pads were extracted with methanol and analyzed by gas chromatography with flame ionization detector using an internal standard. The limits of reliable measurement extended from 2 µg to 2 mg per sample.

Statistics:

An estimate of the ratio of 2,4- to 2,6-DNT total metabolites in the urine of the workers over the entire collection period was obtained by weighed linear regression of the former values upon the latter.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The urine of the workers contained more metabolites than would have resulted from the dinitrotoluene present in the inhaled air, indicating dermal
absorption.
Wiping of skin suspected of being contaminated (mainly hands and forehead) showed levels from "not detected" to 179.5 μg 2,4-DNT. Wiping of environmental surfaces such as a ample valve handle of washer showed levels from "not detected" to 433.2 µg of 2,4-DNT.

Details on excretion:

The ratio of 2,4- to 2,6-DNT in the urinary of the workers was not significantly different from the ratio of the isomers in the material to which the workers were exposed.
No DNT or DNT metabolites were detected in urine from the three researchers at the plant for the study, despite the fact that such materials were observed in specimens obtained from at least three of four office employees.
Excretion of metabolites peaked near the end of the workshift, but declined to either very low or undetectable concentrations by the start of work the following day. The calculated half-times for elimination of total DNT-related material detected in urine ranged from 0.9 to 2.7 hours (1. men: 0.88 hours, 2. men: 2.63 hours, woman: 1. measure 2.29 hours and 2. measure 2.76 hours), and those of individual metabolites from 0.8 to 4.5 hours.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The main metabolites found in human urine were 2,4-dinitrobenzoic acid (52.5% in men and 28.8% in woman) and 2-amino-4-nitrobenzoic acid
(about 37% in men and woman). Furthermore, 2,4- and 2,6-dinitrobenzylglucuronide (9.5% in men and 33.3% in woman) and 2(N-acetyl)amino-4-
nitrobenzoic acid (0.8% in men and 0.3% in woman) were found.
In all, the amount by which men exceeded women with respect to the dinitrobenzoic acids is almost exactly that by which women exceeded men in regard to the dinitrobenzyl glucuronides.