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2,4,5-Trimethylanilin
(CAS-Nr.: 137-17-7)
und sein Hydrochlorid
(CAS-N r.: 21436-97-5)

Ausgabe: März 2001
Stand. November 2000

Preamble:

This document is mainly based on the criteria document of the German MAK Commission dating form 1993 [a] and the IARC Monograph [b]. All numerical citations refer to the citations in the document of the German MAK Commission [a].

2,4,5-trimethylaniline and its hydrochloride are inducers of methaemoglobinemia; they furthermore lead to damages in liver and lung. 2,4,5-trimethylaniline is a metabolite of the red dye Ponceau 3R [c].

Genotoxicity:

2,4,5-trimethylaniline has proved to be mutagenic in the Ames-Test after metabolic activation as well as in a wing spot test in Drosophila and in a mutation test on rat fibroblasts in culture (Table 1). A DNA damaging activity of 2,4,5-trimethylaniline could be shown neither in V79 cells in vitro (Table 1) nor in rat liver in vivo (Table 2).

Table 1: Results of genotoxicity tests in vitro

Table 2: Results of genotoxicity tests in vivo

Carcinogenicity:

In chronic carcinogenicity studies on rats (CD, F 344) and mice (CD-1, B6C3F1) with application in the feed 2,4,5-trimethylaniline hydrochloride proved to be tumorigenic in both species. Localisations of the tumors are mainly the liver and to a lesser extent also the lung. The substance is hepatotoxic leading to liver hyperplasia and to neoplastic liver nodules.

*) P < 0,025

Tumors: increased tumor incidences in liver

*) P = 0.035
**) P = 0.025
***) P = 0.001
****) P < 0.001

Summary:

Genotoxicity:

Since the only available in vivo genotoxicity test, a rat liver DNA-damage assay after oral application of 988 mg/kg bw to female rats using alkaline elution for detection , yielded a negative result, according to the EU classification criteria no classification of 2,4,5- trimethylaniline and its hydrochloride is warranted (M:-).

Carcinogenicity:

The chronic oral application of 2,4,5-trimethylaniline has led to the development of carcinoma in liver and lung in rats and mice. The liver tumors are presumably a consequence of the hepatotoxicity of the substance since DNA damage in the liver could not be demonstrated in female rats after acute oral application of the substance. Besides the liver tumors the substance led to the development of lung tumors in F 344 rats and CD-1 mice. No lung tumors were detected in CD-rats (higher dosage but only 18 months treatment) and in B6C3F1 mice (dosage much lower than for CD-1 mice). Taking together the development of tumors in 2 species and the mutagenic potential in vitro 2,4,5- trimethylaniline should according to the EU-classification criteria classified as Carc. Cat. 2 (C:2).

Reproductive Toxicity/Fertility:

Due to the lack of data the substance can not be classified (RF: -). Reproductive Toxicity/Developmental Effects:

Due to the lack of data the substance can not be classified (RE: -). References:

[1] Greim, H. (Hrsg.): Occupational Toxicants. Critical Data Evaluation for MAK Values and Classification of Carcinogens. Vol. 4, 335-340 (1992)

[2] WHO-IARC: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol. 27, 177-188 (1982)

[3] Hartman, C.P., Andrews, A.W., Chung, K.-T.: Production of a mutagen from Ponceau 3R by a human intestinal anaerobe. Infection and Immunity 23, 686-689 (1979) Kitchin, K.T., Brown, J.L.: Doseresponse relationship for rat liver DNA damage caused by 49 rodent carcinogens. Toxicology 88, 31-49 (1994).

Further data concerning other toxicological endpoints:

Acute toxicity: hydrochloride LD50 p.o. rat 1585 mg/kg bw [1] due to methaemoglobinemia upgraded classification: T, R 23/24/25 Irritation potential: no data

[1] Lindstrom, H.V. et al.: The toxicity and metabolism of mesidine and pseudocumidine in rats. J. Pharmacol. Exp. Ther. 167, 223-234 (1969)

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