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Basic toxicokinetics

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basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented publications, acceptable for assessment

Data source

Referenceopen allclose all

Reference Type:
other: PhD Thesis
Reference Type:
other: Abstract
Reference Type:
The in vivo oxidative metabolism of 2,4- and 2,6-Dimethylaniline in the dog and rat
Short CR, et al.
Bibliographic source:
Toxicology 57, 45-58
Reference Type:
secondary source
The in vivo oxidative metabolism of 2,4- and 2,6 dimethylaniline in the dog and the rat
Short CR, et al.
Bibliographic source:
Toxicology 57, 45-58 (1989), cited in: IARC Monograph 57, 328 (1993)

Materials and methods

Objective of study:
Test guideline
no guideline followed
Principles of method if other than guideline:
The purpose of the investigation was to determine whether species differences in the oxidative metabolism of 2,4-DMA and 2,6-DMA could be related to species specific hepatotoxicities.
GLP compliance:

Test material

Details on test material:
- Name of test material (as cited in study report): 2,6-dimethylaniline
- Analytical purity: >99 %
- Supplier Aldrich Chemical Co., Inc.

Test animals

Fischer 344
Details on test animals and environmental conditions:
- Source: Hilltop Lab Animals, Inc. (Scottsdale, PA)
- Age at study initiation: 12 weeks
- Individual metabolism cages: yes/no
- Diet: Purina Rat Chow ad libitum
- Water: ad libitum

- standard laboratory conditions

Administration / exposure

Route of administration:
oral: gavage
corn oil
Details on exposure:
2,4-DMA (group 1-4);
2,6-DMA (group 5-8)
Duration and frequency of treatment / exposure:
10 days
Doses / concentrations
Doses / Concentrations:
2,6-DMA: 262.5 mg/kg bw
No. of animals per sex per dose:
16 rats in total, to each of 8 groups
Control animals:
Positive control:
not done
Details on study design:
- Dose selection rationale: test substances were equal to 25% of their respective LD50 values (LD50, oral 2,4-DMA = 467 mg/kg ; LD50, oral 2,6-DMA = 1050 mg/kg)
Details on dosing and sampling:
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: day 1 and 10
- From how many animals: 2, samples pooled
- Method type(s) for identification: GC-MS

Analysis of variance and Dunnett's test were used to compare the effects of PB, 3MC and SKF-525A on urinary excretory products of 2,4- and 2,6-DMA on Days 1 and 10 of treatment. A paired t-test was used to compare the effect of length of treatment (Day 1 vs. Day 10) on urinary excretory products within each rat and dog treatment group (10) . Differences were accepted at the (P < 0.05) level.

Results and discussion

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:
2,4-DMA was excreted in the urine of rats as the parent compound, N-acetyl-4-amino-3-methylenzoic acid (AAMBA) or as the sulfate or glucuronide conjugates of these compounds. Trace levels of N,2,4-trimethylaniline were also detected, but at levels too low to permit quantitation. There was no significant difference in the total excretion of parent compound or AAMBA between Days 1 and 10 in rats treated with 2,4-DMA only. Phenobarbital treatment produced inappetence, marked weight loss, an unthrifty appearance, chromodacryorrhea, and death in 50 % of the rats by was Day 5. Therefore no data was available for this group except on Day 1. Histopathological examination of the livers from animals of this group sacrificed on Day 5 revealed no remarkable lesions. Treatment with 3-MC caused an increase in the metabolite to parent (M/P) ratio on Day 1 but the comparison of this ratio between Group 3 and Group 1 on Day 10 was not a significant. However, there was a decrease in the M/P ratio when comparing Day 10 to Day 1. Treatment with SKF-525A did not alter the amount of AAMBA compared to Group 1 on Day 1 or after 10 days of treatment. None of the treatments caused any other metabolite to be detected at any time.
2,6-DMA was excreted in the urine of rats as the parent compound, 4-hydroxy-2,6-DMA, (4-HDMA) and a trace level of N,2,6-trimethylaniline was occasionally detected. In rats receiving 2,6-DMA only, 4-HDMA was the major excretory product on both Days 1 and 10 . Phenobarbital treatment reduced the amount of 2,6-DMA excreted on Day 1 but did not alter the amount of 4-HDMA appearing in urine. Combined treatment with PB and 2,6-DMA did cause weight loss and an unthrifty appearance, but signs of toxicity took longer to develop and were less severe than for the PB: 2,4-DMA group. Treatment with 3-MC caused an increase in the M/P ratio on Day 1, and by Day 10 it had markedly decreased the excretion of parent compound and increased the M/P ratio. Treatment with SKF-525A did not affect 2,6-DMA excretion on either the first or tenth days. There was no effect on 4-HDMA excretion on Day 1, but 10 days of treatment caused a slight decrease, compared to 2,6-DMA excretion.

Any other information on results incl. tables

The test substance is excreted either unchanged or as the 4-hydroxy metabolite or as conjugates of both (sulfate and glucuronic acid). Phenobarbital and 3 -methylcholanthrene decreased the amount of excreted parent compound and increased the excretion of main metabolites (increase in main metabolite to parent ratio). Repeated administration of either 2,4 DMA or 2,6 DMA did not result in significant effects, indicating that xylidine does not induce its own metabolism. The fact that 3 -MC increased the urine concentration of the main metabolite 4-hydroxy-DMA suggests that 4-hydroxylation is Cyt P450 dependent.

Applicant's summary and conclusion