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Toxicological information

Basic toxicokinetics

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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

Constituent 1
Chemical structure
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.