Trimethylamine, N-oxide

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

The results of the in vitro analysis are inconclusive and an in vivo study is proposed.  At this time, it is not proposed to identify trimethylamine N-oxide as mutagenic.

Additional information

in vitro gene mutation study in bacteria

The results of a GLP-compliant OECD TG 471 study for bacterial reverse mutation indicate the test item, trimethylamine N-oxide dihydrate, is not mutagenic under the conditions of this assay.  In two independent experiments, trimethylamine N-oxide dihydrate was exposed to S. typhimurium TA 1535, TA 1537, TA 98 and TA 100 as well as E. coli WP2 uvr A both with and without metabolic activation at a maximum concentration of 5000 µg/plate. The negative and strain-specific positive control values were within the laboratory historical control data ranges indicating that the test conditions were adequate and that the metabolic activation system functioned properly. All bacterial strains showed negative responses to trimethylamine N-oxide dihydrate over the entire dose-range, i.e. no biologically relevant dose-related increase in the number of revertants in two independently repeated experiments.

 

in vitro cytogenicity - micronucleus study

The results of a GLP-complaint OECD TG 487 study for the ability to induce mammalian cell micronuclei indicate the test item, trimethylamine N-oxide dihydrate, is not clastogenic or aneugenic in human lymphocytes under the experimental conditions of this assay.  In two independent experiments, trimethylamine N-oxide dihydrate was exposed to human lymphocytes both with and without metabolic activation at a maximum concentration of 1111 µg/mL. The positive control chemicals, mitomycin C, colchicine and cyclophosphamide all produced a statistically significant increase in the number of binucleated cells with micronuclei. The positive control chemical colchicine produced a statistically significant increase in the number of binucleated cells with micronuclei in at least one experiment. It was therefore concluded that the test conditions were adequate and that the metabolic activation system (S9-mix) functioned properly.  The test system was determined to be valid and trimethylamine N-oxide dihydrate, is not clastogenic or aneugenic in human lymphocytes under the experimental conditions of this assay.

 

in vitro gene mutation study in mammalian cells

The results of a GLP-compliant OECD TG 490 study using the mouse lymphoma L5178Y test system indicate in the absence of S9-mix the test item, trimethylamine N-oxide dihydrate, induced increases in the mutant frequency after the short (3 hour) treatment period.  The test was performed with and without metabolic activation with a 3 hour treatment period up to a maximum concentration of 1111 µg/mL. 

 

In the absence of S9-mix, the test material induced increases in the mutant frequency after the short (3 hour) treatment period. The increases in the mutant frequency were considered to be biologically relevant.  In the presence of S9-mix, the test material did not induce a biologically relevant increase in the mutant frequency.  Therefore, in this valid test, trimethylamine N-oxide dihydrate is mutagenic in the mouse lymphoma L5178Y test system under the experimental conditions described in this report.  

 

In vivo mammalian somatic and germ cell study – gene mutation

Due to the positive result reported with the in vitro gene mutation study using the mouse lymphoma L5178Y test system, the registrant has proposed conducting an in vivo Transgenic Rodent Somatic and Germ Cell Gene Mutation Assays (OECD TG 488).

Justification for classification or non-classification

The results of the in vitro analysis are inconclusive and an in vivo study is proposed.  At this time, it is not proposed to identify trimethylamine N-oxide as mutagenic.