Evaluation of the in vivo genotoxicity of the structural analogues 2,6-diaminotoluene and 2,4-diaminotoluene using the rat micronucleus test and rat liver UDS assay.
The two structural isomers 2,4- and 2,6-diaminotoluene (DAT) differ in their carcinogenic properties; the 2,4-isomer is carcinogenic in rats and mice, whereas the 2,6-isomer has been reported to be non-carcinogenic. Both isomers were reported to be mutagenic in Salmonella typhimurium in the presence of S9, which was confirmed in the present study before in vivo assays were commenced. Both isomers were tested in the rat bone marrow micronucleus test and the rat liver UDS test to investigate how well these assays discriminate between the carcinogenic and the non-carcinogenic isomer. In the micronucleus test both isomers gave weakly positive results; however, with the carcinogen 2,4-DAT this weak effect was only detectable at very toxic doses and therefore the biological relevance of this result is questionable. Thus, the micronucleus test did not discriminate correctly between the carcinogen and the non-carcinogen. With the liver UDS test, discrimination was achieved but the positive effect seen for the carcinogenic isomer was weak and dependent on the method of preparation of the dosing suspensions. The results are discussed in relation to the carcinogenicity data on both compounds. It is concluded that although both isomers are potent genotoxins in vitro they exert their genotoxic potential only weakly in vivo and convincing discrimination between the carcinogenic and non-carcinogenic isomer was not demonstrated.
George
E
E
Genetic and Reproductive Toxicology, Glaxo Group Research Ltd., Ware, UK.
Westmoreland
C
C
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D015197:Carcinogenicity Tests; D004247:DNA / Q000096:biosynthesis* / Q000187:drug effects; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D015162:Micronucleus Tests; D010655:Phenylenediamines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains
D010655:Phenylenediamines; D004247:DNA; C025235:2,6-diaminotoluene; C010914:2,4-diaminotoluene