The in vivo oxidative metabolism of 2,4- and 2,6-dimethylaniline in the dog and rat

Comprehensive urinary metabolite profiles of workers exposed to aniline, 2,4-dimethylaniline, and 2-methylaniline

“…2. 2,4-Dimethylaniline: In the participants in the present study, the unchanged compounds and all metabolites detected in rats and dogs 6 other than N -methyl-2,4-dimethylaniline (methyl group-adduct, D8) were found. These included: N -acetyl-4-carboxy-2-methylaniline (methyl group-oxide + N -acetylated, D7), 37.2%; 6-hydroxy-2,4-dimethylaniline (ring-hydroxylated, D3), 36.5%; 2,4-dimethylaniline (unchanged, D1) 14.8%; 4-carboxy-2-methylaniline (methyl group-oxide, D6), 5.7%; N -acetyl-5-hydroxy-2,4-dimethylaniline (ring-hydroxylated + N -acetylated, D5), 4.5%; and N -acetyl-2,4-dimethylaniline ( N -acetylated, D2), 1.0%.…”

“…These included: N -acetyl-4-carboxy-2-methylaniline (methyl group-oxide + N -acetylated, D7), 37.2%; 6-hydroxy-2,4-dimethylaniline (ring-hydroxylated, D3), 36.5%; 2,4-dimethylaniline (unchanged, D1) 14.8%; 4-carboxy-2-methylaniline (methyl group-oxide, D6), 5.7%; N -acetyl-5-hydroxy-2,4-dimethylaniline (ring-hydroxylated + N -acetylated, D5), 4.5%; and N -acetyl-2,4-dimethylaniline ( N -acetylated, D2), 1.0%. Short et al 6 showed that there was a difference in the types of metabolites between rats and dogs: N -acetyl-4-carboxy-2-methylaniline (D7) accounted for approximately 60%, and 6-hydroxy-2,4-dimethylaniline (D3) was less than the LOQ in rats, whereas the inverse applied in dogs, with 6-hydroxy-2,4-dimethylaniline (D3) representing approximately 90%, and N -acetyl-4-carboxy-2-methylaniline (D7) less than the LOQ. The proportions of metabolites were more evenly dispersed in the human workers than in rats or dogs.…”

Comprehensive urinary metabolite profiles of workers exposed to aniline, 2,4-dimethylaniline, and 2-methylaniline

“…2. 2,4-Dimethylaniline: In the participants in the present study, the unchanged compounds and all metabolites detected in rats and dogs 6 other than N -methyl-2,4-dimethylaniline (methyl group-adduct, D8) were found. These included: N -acetyl-4-carboxy-2-methylaniline (methyl group-oxide + N -acetylated, D7), 37.2%; 6-hydroxy-2,4-dimethylaniline (ring-hydroxylated, D3), 36.5%; 2,4-dimethylaniline (unchanged, D1) 14.8%; 4-carboxy-2-methylaniline (methyl group-oxide, D6), 5.7%; N -acetyl-5-hydroxy-2,4-dimethylaniline (ring-hydroxylated + N -acetylated, D5), 4.5%; and N -acetyl-2,4-dimethylaniline ( N -acetylated, D2), 1.0%.…”

“…These included: N -acetyl-4-carboxy-2-methylaniline (methyl group-oxide + N -acetylated, D7), 37.2%; 6-hydroxy-2,4-dimethylaniline (ring-hydroxylated, D3), 36.5%; 2,4-dimethylaniline (unchanged, D1) 14.8%; 4-carboxy-2-methylaniline (methyl group-oxide, D6), 5.7%; N -acetyl-5-hydroxy-2,4-dimethylaniline (ring-hydroxylated + N -acetylated, D5), 4.5%; and N -acetyl-2,4-dimethylaniline ( N -acetylated, D2), 1.0%. Short et al 6 showed that there was a difference in the types of metabolites between rats and dogs: N -acetyl-4-carboxy-2-methylaniline (D7) accounted for approximately 60%, and 6-hydroxy-2,4-dimethylaniline (D3) was less than the LOQ in rats, whereas the inverse applied in dogs, with 6-hydroxy-2,4-dimethylaniline (D3) representing approximately 90%, and N -acetyl-4-carboxy-2-methylaniline (D7) less than the LOQ. The proportions of metabolites were more evenly dispersed in the human workers than in rats or dogs.…”

PFAS Biotransformation Pathways: A Species Comparison Study

“…True species differences do exist in the metabolism of xenobiotics. For example, the metabolism of 2,4-dimethylaniline (2,4-DMA) was compared in vivo in the rat and dog [ 74 ]. The major metabolite found in the rat but not in the dog was N-acetyl-4-amino-3-methyl benzoic acid (AAMBA).…”

Mutagenic properties of dimethylaniline isomers in mice as evaluated by comet, micronucleus and transgenic mutation assays

“…That is to say, only 3,4- and 3,5-DMA caused DNA damage in the bone marrow, while they were shown to cause relatively weak DNA damage in the lung. As for 2,4- and 2,6-DMA, a species difference in metabolic pathways was found between rats and dogs, and general toxicity for repeated dosing was stronger for 2,4-DMA in rats and for 2,6-DMA in dogs [ 32 ]. Because isomer differences and species differences likely play a role in DMA toxicity, further investigation is necessary to gain a better understanding of the relationship between DMAs and carcinogenicity in humans.…”

Comprehensive urinary metabolite profiles of workers exposed to aniline, 2,4-dimethylaniline, and 2-methylaniline

“…2. 2,4-Dimethylaniline: In the participants in the present study, the unchanged compounds and all metabolites detected in rats and dogs 6 other than N -methyl-2,4-dimethylaniline (methyl group-adduct, D8) were found. These included: N -acetyl-4-carboxy-2-methylaniline (methyl group-oxide + N -acetylated, D7), 37.2%; 6-hydroxy-2,4-dimethylaniline (ring-hydroxylated, D3), 36.5%; 2,4-dimethylaniline (unchanged, D1) 14.8%; 4-carboxy-2-methylaniline (methyl group-oxide, D6), 5.7%; N -acetyl-5-hydroxy-2,4-dimethylaniline (ring-hydroxylated + N -acetylated, D5), 4.5%; and N -acetyl-2,4-dimethylaniline ( N -acetylated, D2), 1.0%.…”

“…These included: N -acetyl-4-carboxy-2-methylaniline (methyl group-oxide + N -acetylated, D7), 37.2%; 6-hydroxy-2,4-dimethylaniline (ring-hydroxylated, D3), 36.5%; 2,4-dimethylaniline (unchanged, D1) 14.8%; 4-carboxy-2-methylaniline (methyl group-oxide, D6), 5.7%; N -acetyl-5-hydroxy-2,4-dimethylaniline (ring-hydroxylated + N -acetylated, D5), 4.5%; and N -acetyl-2,4-dimethylaniline ( N -acetylated, D2), 1.0%. Short et al 6 showed that there was a difference in the types of metabolites between rats and dogs: N -acetyl-4-carboxy-2-methylaniline (D7) accounted for approximately 60%, and 6-hydroxy-2,4-dimethylaniline (D3) was less than the LOQ in rats, whereas the inverse applied in dogs, with 6-hydroxy-2,4-dimethylaniline (D3) representing approximately 90%, and N -acetyl-4-carboxy-2-methylaniline (D7) less than the LOQ. The proportions of metabolites were more evenly dispersed in the human workers than in rats or dogs.…”

PFAS Biotransformation Pathways: A Species Comparison Study

“…True species differences do exist in the metabolism of xenobiotics. For example, the metabolism of 2,4-dimethylaniline (2,4-DMA) was compared in vivo in the rat and dog [ 74 ]. The major metabolite found in the rat but not in the dog was N-acetyl-4-amino-3-methyl benzoic acid (AAMBA).…”

Mutagenic properties of dimethylaniline isomers in mice as evaluated by comet, micronucleus and transgenic mutation assays

“…That is to say, only 3,4- and 3,5-DMA caused DNA damage in the bone marrow, while they were shown to cause relatively weak DNA damage in the lung. As for 2,4- and 2,6-DMA, a species difference in metabolic pathways was found between rats and dogs, and general toxicity for repeated dosing was stronger for 2,4-DMA in rats and for 2,6-DMA in dogs [ 32 ]. Because isomer differences and species differences likely play a role in DMA toxicity, further investigation is necessary to gain a better understanding of the relationship between DMAs and carcinogenicity in humans.…”

Comprehensive urinary metabolite profiles of workers exposed to aniline, 2,4-dimethylaniline, and 2-methylaniline

“…2. 2,4-Dimethylaniline: In the participants in the present study, the unchanged compounds and all metabolites detected in rats and dogs 6 other than N -methyl-2,4-dimethylaniline (methyl group-adduct, D8) were found. These included: N -acetyl-4-carboxy-2-methylaniline (methyl group-oxide + N -acetylated, D7), 37.2%; 6-hydroxy-2,4-dimethylaniline (ring-hydroxylated, D3), 36.5%; 2,4-dimethylaniline (unchanged, D1) 14.8%; 4-carboxy-2-methylaniline (methyl group-oxide, D6), 5.7%; N -acetyl-5-hydroxy-2,4-dimethylaniline (ring-hydroxylated + N -acetylated, D5), 4.5%; and N -acetyl-2,4-dimethylaniline ( N -acetylated, D2), 1.0%.…”

“…These included: N -acetyl-4-carboxy-2-methylaniline (methyl group-oxide + N -acetylated, D7), 37.2%; 6-hydroxy-2,4-dimethylaniline (ring-hydroxylated, D3), 36.5%; 2,4-dimethylaniline (unchanged, D1) 14.8%; 4-carboxy-2-methylaniline (methyl group-oxide, D6), 5.7%; N -acetyl-5-hydroxy-2,4-dimethylaniline (ring-hydroxylated + N -acetylated, D5), 4.5%; and N -acetyl-2,4-dimethylaniline ( N -acetylated, D2), 1.0%. Short et al 6 showed that there was a difference in the types of metabolites between rats and dogs: N -acetyl-4-carboxy-2-methylaniline (D7) accounted for approximately 60%, and 6-hydroxy-2,4-dimethylaniline (D3) was less than the LOQ in rats, whereas the inverse applied in dogs, with 6-hydroxy-2,4-dimethylaniline (D3) representing approximately 90%, and N -acetyl-4-carboxy-2-methylaniline (D7) less than the LOQ. The proportions of metabolites were more evenly dispersed in the human workers than in rats or dogs.…”

PFAS Biotransformation Pathways: A Species Comparison Study

“…True species differences do exist in the metabolism of xenobiotics. For example, the metabolism of 2,4-dimethylaniline (2,4-DMA) was compared in vivo in the rat and dog [ 74 ]. The major metabolite found in the rat but not in the dog was N-acetyl-4-amino-3-methyl benzoic acid (AAMBA).…”

Mutagenic properties of dimethylaniline isomers in mice as evaluated by comet, micronucleus and transgenic mutation assays

“…That is to say, only 3,4- and 3,5-DMA caused DNA damage in the bone marrow, while they were shown to cause relatively weak DNA damage in the lung. As for 2,4- and 2,6-DMA, a species difference in metabolic pathways was found between rats and dogs, and general toxicity for repeated dosing was stronger for 2,4-DMA in rats and for 2,6-DMA in dogs [ 32 ]. Because isomer differences and species differences likely play a role in DMA toxicity, further investigation is necessary to gain a better understanding of the relationship between DMAs and carcinogenicity in humans.…”