Toxicology and Carcinogenesis Studies ofN,N-Dimethylaniline (CAS No. 121-69-7) in F344/N Rats and B6C3F1Mice(Gavage Studies)
Chemical Formula: C8H1N
N,N-Dimethylanilineis used as a chemical intermediate in the synthesis of dyestuffs. Toxicologyand carcinogenesis studies were conducted by administeringN,N-dimethylaniline (greater than 98% pure) in corn oil by gavage togroups of F344/N rats and B6C3F1 mice of each sex for 2 weeks, 13 weeks,or 2years. Genetic toxicology studies were conducted in Salmonellatyphimurium, mouse lymphoma cells, and Chinese hamster ovary (CHO)cells.
In the 2-weekstudies, doses were 94-1,500mg/kg; deaths of rats and mice were observed in groups given doses of 750 or1,500 mg/kg. The final mean body weights of male rats that received 375 or750mg/kg were 15% or 47% lower than that of vehicle controls; final mean bodyweights of other groups of rats and mice were similar to those of vehiclecontrols. Compound-relatedclinical signs observed included cyanosis in rats and lethargy and tremors inrats and mice. Splenomegaly occurred in nearly all dosed groups of rats andmice, and the incidences were dose related.
In the 13-weekstudies, doses were 32-500mg/kg; no compound-related deaths occurred. The final mean body weightsofmale rats that received 250 or 500 mg/kg were 15% or 27% lower than that ofvehicle controls. The final mean body weights of all groups of dosed femalerats and male and female mice were within 12% of those of vehicle controls.Compound-relatedclinical signs included lethargy in rats and mice and cyanosis in rats.Splenomegaly was observed in all dosed groups of rats and mice; the severitywas dose related. Compound-relatedextramedullary hematopoiesis and hemosiderosis occurred in the kidney ortestisof dosed rats and liver and spleen of dosed rats and mice.
Two-yearstudies were conducted by administering 0, 3, or 30 mg/kgN,N-dimethylanilinein corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 rats ofeach sex. The lower dose was selected to be one-tenththe higher dose to increase the likelihood that one dose would cause only aminimal nonneoplastic response. Groups of 50 mice of each sex wereadministered 0, 15, or 30 mg/kg on the same schedule.
Body Weight and Survival in the Two-YearStudies:
Mean body weights of vehicle control and dosed rats and mice weresimilar throughout the studies. Survival rates of all respective groups weresimilar after 2 years, except for the lowered survival of vehicle controlfemale rats (vehicle control, 21/50; low dose 32/50; high dose, 36/50).This may reflect the large number (24/50) of vehicle control female rats killedwhen observed to be in a moribund state. Final survival for other groups wasasfollows: male rats--29/50; 32/50; 28/50; male mice--34/50;30/50; 34/50; female mice--35/50;39/50; 33/50.
Nonneoplastic and Neoplastic Effects in the Two-YearStudies:
In these 2-yearstudies, the spleen was the expected site of chemical-relatedeffects. Fatty metamorphosis and fibrosis in the spleen of high dose male ratswere increased (fatty metamorphosis: vehicle control, 0/49; low dose, 1/49;high dose, 10/50; fibrosis: 5/49; 2/49; 22/50). Splenic hemosiderosis andhematopoiesis were present at an incidence greater than 85% in all groups ofrats; however, the severity of the lesions was greater in dosed groups than invehicle controls. Sarcomas of the spleen were seen in 3/50 high dose malerats, and an osteosarcoma was seen in another high dose male rat. Oneadditional high dose male rat had a sarcoma of the thymus. Splenic sarcomasare uncommon in corn oil vehicle control male F344/N rats (NTP historicalincidence 3/2,081, 0.1%), and thus, these neoplasms in high dose male rats(4/50, 8%) were considered to be chemically related.
Lower incidences of mononuclear cell leukemia (which apparently originatesinthe spleen) were seen in dosed male and female rats than in vehicle controls(male: 13/50; 4/50; 3/50; female: 11/50; 7/50; 0/50).
The incidence of squamous cell papillomas of the forestomach in high dosefemale mice was marginally greater than that in vehicle controls (2/50; 2/50;8/50). No malignant forestomach neoplasms were observed.
N,N-Dimethylanilinewas not mutagenic in S. typhimurium strains TA98, TA100, TA1535, orTA1537 in the presence or absence of exogenous metabolic activation. In themouse lymphoma assay, N,N-dimethylaniline produced a positiveresponsewith and without metabolic activation. In CHO cells,N,N-dimethylaniline induced both sister chromatid exchanges (SCEs)andchromosomal aberrations in the presence of exogenous metabolic activation.Without activation, an increase in chromosomal aberrations was observed,but noincrease in SCEs occurred.
Under the conditions of these 2-yeargavage studies, there was some evidence of carcinogenic activity ofN,N-dimethylaniline for male F344/N rats, as indicated by the increasedincidences of sarcomas or osteosarcomas(combined) of the spleen. Therewasno evidence of carcinogenic activity of N,N-dimethylanilinefor female F344/N rats given 3 or 30 mg/kg body weight by gavage for 2 years.There was no evidence of carcinogenic activity ofN,N-dimethylaniline for male B6C3F1 mice given 15 or 30 mg/kg bodyweight by gavage for 2 years. There was equivocal evidence ofcarcinogenicactivity of N,N-dimethylaniline for female B6C3F1 mice, asindicatedby an increased incidence of squamous cell papillomas of the forestomach. Bothrats and mice could have tolerated doses higher than those used in thesestudies.
There were decreased incidences of mononuclear cell leukemia in dosedmale andhigh dose female rats. Compound-related splenic fibrosis, hemosiderosis, andfatty metamorphosis were increased in male rats.
Synonyms: dimethylaminobenzene; N,N-dimethylbenzeneamine;dimethylaniline; dimethylphenylamine; N,N-dimethylphenylamine
Report Date: October 1989