o-anisidine

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

year of publication: 2002

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Only secondary literature

Data source

Reference

Reference Type:

review article or handbook

Title:

European Union Risk Assessment Report - o-Anisidin

Author:

European Chemicals Bureau

Year:

2002

Bibliographic source:

European Commission, Joint Research Center, EUR 19834 EN, 2nd Priority list, Volume 15

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

o-anisidine

EC Number:

201-963-1

EC Name:

o-anisidine

Cas Number:

90-04-0

Molecular formula:

C7H9NO

IUPAC Name:

2-methoxyaniline

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

From toxicological studies the absorption via the dermal, oral and inhalation pathways are assumed.

Details on excretion:

The substance is excreted fast (>90% within 96h; majority in the first 24 h) mainly in the urine.

Any other information on results incl. tables

Oral, dermal and resorption after inhalational exposure can be assumed as systemic effects were observed in toxicological studies. Metabolism seems to be comparable to other aromatic amines: N-hydroxylation and N- or O-acetylation take place as well as peroxidation occurs via enzymes like prostaglandin-H-synthase. Furthermore, O-demethylation may appear.

These different metabolism pathways mentioned are supported by findings in diverse studies and some conclusions can be drawn. For example one could assume that the N-hydroxy derivative, maybe responsible for the formation of methaemoglobin due to the known interaction of this group with the haem group of hemoglobin. Or the activation of o-anisidine by N-/O-acetylation can be confirmed by positive mutagenic response in bacterial gene mutation assays with Salmonella typhimurium strains containing elevated levels of N- or O-acetyltransferase levels. There are in vitro studies showing that horseradish peroxidase (used as model enzyme) induces the formation of reactive intermediates of o-anisidine. This is also suggested to be true for prostaglandin-H synthase, which is broadly distributed in mammalian tissues including the urinary bladder. Incubation of o-anisidine with the thyroid peroxidase, its endogenous subtrates guiacol and iodide as well as H2O2, the transformation of guiacol and iodide was efficiently inhibited (IC50: 1.9 µM). in another in vitro study O-demethylation occurred using microsomes from rat liver (relative rate of o-anisidine as compared to the formation of formaldehyde from N,N-dimethylaniline: 13%).

The major excretion pathway was identified in another toxicokinetic study (OECD Guideline 417) using a dye containing radioactive carbon. The study summarieses as follows: "..., the dye¹⁴C-FAT 923 67/A was orally administered to Wistar rats (single oral administration at a target dose level of 7.4 mg/kg bw). Probably as a result of the bacterial breakdown of this compound in the gastrointestinal tract,o-anisidine could be detected in the plasma of male rats (1.5% of the administered¹⁴C-activity characterised as o-anisidine [0.017 µg/g]), in the urine of male rats (0.14% of the administered ¹⁴C-activity) and in faeces of male and female rats (0.9 or 1.1% of the administered¹⁴C-activity,resp.). Within 96 hours more than 93% of the administered ¹⁴C-activity were excreted mainly via urine; the major amount was excreted within the first 24 hours."

Applicant's summary and conclusion

Conclusions:

Oral, dermal and resorption after inhalational exposure can be assumed as systemic effects were observed in toxicological studies.
Metabolism seems to be comparable to other aromatic amines: N-hydroxylation and N- or O-acetylation take place as well as peroxidation occurs via enzymes like prostaglandin-H-synthase (note: o-anisidine is also a substrate of thyroid peroxidase). Furthermore, O-demethylation may appear. The urine is proved to be the main exretion route, as >90% of the applied 14C-activity was excreted within 96 h in rats in one toxicokinetic study.