NTP toxicity studies of toxicity studies of 2,4-decadienal (CAS No. 25152-84-5) administered by gavage to F344/N Rats and B6C3F1 mice

Abstract

2,4-Decadienal is used as a synthetic flavoring and fragrance material and has been evaluated as a corrosion inhibitor for steel in oil field operations. 2,4-Decadienal was nominated by the National Cancer Institute for toxicity testing because the dienaldehydes occur naturally in a variety of foods and food components, are used as food additive/flavoring agents, and the potential for human exposure is high. In the toxicity studies, male and female F344/N rats and B6C3F1 mice received 2,4-decadienal (at least 93% pure) in corn oil by gavage for 2 weeks or 3 months. Genetic toxicology studies were conducted in Salmonella typhimurium, rat and mouse bone marrow cells, and mouse peripheral blood erythrocytes. In the 2-week studies, groups of five male and five female rats and mice received 2,4-decadienal in corn oil by gavage at doses of 0, 45, 133, 400, 1,200, or 3,600 mg 2,4-decadienal/kg body weight 5 days per week for 16 days. All animals in the 3,600 mg/kg groups were found dead or sacrificed moribund by day 3 (rats) or day 9 (mice). One 133 mg/kg female rat was found dead on day 8, and one male and one female mouse in the 1,200 mg/kg groups were found dead on days 12 and 16, respectively. At 1,200 mg/kg, treatment-related ulceration of the forestomach was observed in male and female rats and mice. Focal necrosis of the forestomach occurred in a 1,200 mg/kg female mouse. Mean body weights of all 1,200 mg/kg groups were less than those of the vehicle controls, and 1,200 mg/kg female mice lost weight during the study. Diarrhea, lethargy, abnormal breathing (rats), and thinness (mice) occurred in the 1,200 and 3,600 mg/kg groups. Gross lesions seen at necropsy included ulcerations of the forestomach in 1,200 mg/kg rats and 1,200 and 3,600 mg/kg mice. Adhesions involving the stomach and other abdominal organs were also seen in 1,200 and 3,600 mg/kg mice. In the 3-month studies, groups of 10 male and 10 female rats and mice received 2,4-decadienal in corn oil by gavage at doses of 0, 50, 100, 200, 400, or 800 mg 2,4-decadienal/kg 5 days per week for 14 weeks. No chemical-related deaths occurred. Mean body weights of 400 mg/kg male rats and 800 mg/kg male and female rats and male mice were significantly less than those of the vehicle controls. Dosed male and female rats were lethargic after week 7; the severity of the lethargy was dose related. There were changes in the leukon of dosed rats compared to vehicle control rats characterized by decreased leukocyte, lymphocyte, and eosinophil counts and increased neutrophil counts. Spleen weights of 800 mg/kg female rats and thymus weights of 400 and 800 mg/kg female rats were significantly less than those of the vehicle controls. Thymus, spleen, testis, cauda epididymis, and epididymis weights of 800 mg/kg male rats were less than those of the vehicle controls. The incidences of epithelial hyperplasia of the forestomach were significantly greater in 400 and 800 mg/kg male and female rats, 200, 400, and 800 mg/kg male mice, and 800 mg/kg female mice than in the vehicle controls. Incidences of epithelial degeneration of the forestomach were significantly increased in 800 mg/kg rats and the incidence of chronic active inflammation of the forestomach was significantly increased in 800 mg/kg female rats. Incidences of exudate and olfactory epithelial atrophy of the nose were significantly increased in 800 mg/kg male rats, and incidences of olfactory epithelial necrosis occurred in 200 mg/kg or greater mice. Olfactory epithelial hydropic degeneration occurred in a single female mouse from the 100 mg/kg group. 2,4-Decadienal was not mutagenic in any of several strains of S. typhimurium tested with and without liver S9 activation enzymes. Acute bone marrow micronucleus tests in laboratory rodents administered 2,4-decadienal by intraperitoneal injection yielded mixed results. In male rats, a single injection of 2,4-decadienal gave a positive response, but no confirmatory trial was conducted. In male mice, a standard three-injection bone marrow micronucleus experiment yielded negative results but a 48-hour bone marrow analysis after a single dose of 600 mg/kg revealed a small but statistically significant increase in micronucleated polychromatic erythrocytes. Analysis of peripheral blood erythrocytes in these same mice also showed a dose-related increase in micronucleated polychromatic cells, but the increase was insufficient for a positive call and the results of the acute micronucleus assays in mice were judged to be equivocal overall. No increase in the frequency of micronucleated normochromatic erythrocytes was seen in peripheral blood of male or female mice administered 2,4-decadienal by gavage for 3 months. In summary, 2,4-decadienal administration caused decreased body weights and increased incidences of forestomach lesions in the 3-month studies in rats and mice. In addition, treatment-related lesions of the olfactory epithelium were observed in male rats and male and female mice. The no-observed-adverse-effect level was determined to be 100 mg/kg in rats and mice. 2,4-Decadienal was not mutagenic in vitro or in vivo. Synonyms: 2,4-De; deca-2,4-dienal; trans,trans-2,4-decadienal; trans,trans-2,4-decadien-1-al; heptenyl acrolein; RIFM#77-102.