4-nitrotoluene

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: SIDS Initial Assessment Report 2003

Adequacy of study:

other information

Reliability:

other: SIDS Initial Assessment Report 2003

Rationale for reliability incl. deficiencies:

other: No reliability is given as this is a summary entry for the OECD SIDS

Data source

Reference

Reference 1

Reference Type:

secondary source

Title:

4-Nitrotoluene - CAS N°: 99-99-0 - SIDS Initial Assessment Report.

Author:

OECD

Year:

2003

Bibliographic source:

UNEP Publications

Reference 2

Reference Type:

publication

Title:

Pharmacokinetics of xenobiotics: p-nitrotoluene

Author:

Sipes IG, Carter DE

Bibliographic source:

NIEHS-Contract- No. NO1-ES-8-2130

Reference 3

Reference Type:

publication

Title:

National Toxicology Program, NTP Technical report on the toxicology and carcinogenesis studies of p-Nitrotoluene in F344/N rats and B6C3F1 mice

Author:

US Department of Health and Human Services

Year:

2002

Bibliographic source:

NTP technical report No. 498, NIH Publication No. 01-4432

Reference 4

Reference Type:

publication

Title:

Isomer- and sex-specific bioactivation of mononitrotoluenes, Role of enterohepatic circulation

Author:

Chism JP, Rickert DE

Year:

1985

Bibliographic source:

Drug Metab Dispos 13: 651-657

Reference 5

Reference Type:

publication

Title:

The metabolism and excretion of mononitrotoluenes by Fischer 344 rats

Author:

Chism JP, Turner Jr JM, Rickert DE

Year:

1984

Bibliographic source:

Drug Metab Dispos 12: 596-602

Reference 6

Reference Type:

secondary source

Title:

Report 41, Nitrotoluenes

Author:

GDCh-Advisory Committee on Existing Chemicals of Environmental Relevance (BUA

Year:

1989

Bibliographic source:

VCH, Weinheim

Materials and methods

Principles of method if other than guideline:

SIDS Initial Assessment Report 2003

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

4-nitrotoluene

EC Number:

202-808-0

EC Name:

4-nitrotoluene

Cas Number:

99-99-0

Molecular formula:

C7H7NO2

IUPAC Name:

1-methyl-4-nitrobenzene

Results and discussion

Any other information on results incl. tables

OECD SIDS (2003):

Nitrotoluenes are readily absorbed via the gastrointestinal tract, the lungs and, to a lesser extent, via the skin (BUA, 1989). 4-Nitrotoluene is rapidly distributed throughout the body (Sipes and Carter, undated). Excretion takes place principally via the urine (> 80 % within 72 hours), and only small amounts are eliminated in the feces (2 - 5 %). In rats, enterohepatic circulation was also observed.

Excrection via exhaled air, however, does not seem to be a relevant route of elimination (Chism et al., 1984; Chism and Rickert, 1985; U.S. Department for Health and Human Services, 2002).

In the urine of rats, the major metabolites were identified as 4-nitrobenzoic acid (30 - 45 % of the administered dose), 4-acetamidobenzoic acid, and 4-nitrohippuric acid, whereas in mice the main metabolic pathway was ring hydroxylation and conjugation with glucuronide and sulfate. p- Nitrobenzyl mercapturic acid was found only in rats, indicating that a potentially reactive benzylating agent is formed during metabolism of 4-nitrotoluene in rats (U.S. Department for Health and Human Services, 2002).

No relevant differences were found in the urinary metabolite profiles after nine daily doses of 200 mg/kg bw to that seen after a single dose (U.S. Department for Health and Human Services, 2002).

The ratios of urinary 4-nitrobenzoic acid to creatinine and urinary 4-acetamidobenzoic acid to creatinine were followed as biomarkers of exposure in a 2 year carcinogenicity study, and were found to be linearly related to dietary doses of 4-nitrotoluene in rats (U.S. Department for Health and Human Services, 2002).

Involvement of enterohepatic circulation of 4-nitrotoluene metabolites (mainly nitrobenzylglucuronides) was observed in rats. The nitro groups of the metabolites secreted with the bile are reduced by intestinal bacteria and subsequently reabsorbed while generating reactive products in the liver (BUA, 1989).

 

Conclusion

4-Nitrotoluene is rapidly absorbed via skin, gastrointestinal or respiratory tract, and distributed throughout the body. The primary metabolic pathway is side-chain or ring oxidation and conjugation with glucuronic acid and inorganic sulfates with subsequent renal excretion. In rats, the involvement of enterohepatic circulation was also observed.