title: NTP technical report on the toxicity studies of 1,6-Hexanediamine Dihydrochloride (CAS No. 6055-52-3) Administered by Drinking Water and Inhalation to F344/N Rats and B6C3F1 Mice.
abstract: 1,6-Hexanediamine (HDA) is an aliphatic amine that is produced in large volumes in the United States. HDA is widely used as a corrosion inhibitor in lubricants and as an intermediate in the industrial synthesis of paints, resins, inks, and textiles. Toxicity studies of the dihydrochloride salt of HDA (HDDC) were conducted in male and female Fischer 344/N rats and B6C3F1 mice by the drinking water (2-week studies only) and whole-body inhalation routes (2-week and 13-week studies). Animals were evaluated for histopathology, clinical chemistry, hematology, and reproductive toxicity. In addition, the genetic toxicity of HDA was assessed in Salmonella typhimurium and in Chinese hamster ovary cells in vitro; HDDC was evaluated in the mouse micronucleus assay in vivo. In the 2-week drinking water studies, groups of 5 rats of each sex received HDDC at doses of 0.75 to 6.7 mg/mL, and groups of 5 mice of each sex received doses of 0.2 to 3.0 mg/mL for 14 or 15 days. All animals survived to the end of the studies. No gross or microscopic pathologic changes and no clinical abnormalities related to HDDC consumption were seen in any dose group. The only statistically significant change was a slight decrease in absolute and/or relative liver weights of female rats in the 1.7, 5.0, and 6.7-mg/mL treatment groups, in male rats in the 3.0 mg/mL treatment group, and in female mice in the 0.8 mg/mL treatment group. Because there was no significant toxicity in these studies, 13-week drinking water studies were not conducted. In the 2-week inhalation studies, 5 rats and 5 mice of each sex were exposed to 0, 10, 30, 89, 267, or 800 mg HDDC/m(3) for 6-hours per day for 12 days. In the highest exposure group (800 mg/m(3)), all male and female rats, all female mice, and 2 male mice died before the end of the studies. In the remaining groups, there was a dose-dependent depression in body weight gain in male and female mice, but not in rats. Clinical signs were primarily related to upper respiratory tract irritation and included dyspnea and nasal discharge in rats and mice. Absolute and relative liver weights were reduced in some male mice, but this did not occur in a dose- dependent manner. In rats, histopathologic lesions that were considered related to chemical exposure included inflammation and necrosis of laryngeal epithelium as well as focal inflammation and ulceration of the respiratory and olfactory nasal mucosa. In mice, focal areas of inflammation and necrosis were present in the respiratory mucosa of the larynx and trachea in the 2 highest exposure groups. Nasal lesions, including focal inflammation and ulceration, and degeneration and necrosis of the olfactory and respiratory epithelium were also seen in mice. In addition, mild testicular degeneration was present in 2 mice from the highest exposure group (800 mg/m(3)). In the 13-week inhalation studies, 10 rats and 10 mice of each sex were exposed to 0, 1.6, 5, 16, 50, or 160 mg HDDC/m(3) for 6 hours per day, 5 days per week for 13 weeks. In addition special groups of 20 male and 40 female rats and mice (mating trial animals) at each exposure level were included to assess the effect of HDDC on reproduction. All rats and mice in the base-study groups survived to the end of the studies, and there were no exposure-related changes in body weight. In the mating trials, 3 female mice exposed to 16 mg/m(3) and 1 female and 1 male mouse exposed to 50 mg/m(3) died before scheduled termination. These deaths, however, were not considered to be chemical related. In male mice in the base study, liver weights were increased relative to controls in the 2-highest exposure groups. No exposure-related changes in absolute or relative organ weights and no exposure-related clinical signs or gross lesions were seen in either species. In female rats, a dose-related decrease in white blood cell count was observed. Chemical-related microscopic lesions in male and female rats and mice were limited to the upper respiratory tract (larynx and nasal passages) in the 2 highest exposure groups and were similar in both species. These lesions included minimal to mild focal erosion/ulceration, inflammation, and hyperplasia of the laryngeal epithelium as well as degeneration of the olfactory and respiratory nasal epithelium. HDDC caused no significant changes in sperm morphology or in the length of the estrous cycle of rats or mice. In mating trials, HDDC demonstrated no adverse effects on reproduction of rats. The only statistically significant changes in reproductive parameters of mice were a slight increase in gestation length in the 50 mg/m(3) and 160 mg/m(3) exposure groups and a decrease in mean pup weight on Day 21 in the highest exposure group. These changes were not considered to be biologically significant. 1,6-Hexanediamine was not mutagenic in 4 strains of Salmonella typhimurium, and it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. These in vitro tests were conducted with and without exogenous metabolic activation (S9). Negative results were also obtained in an in vivo test that measured the frequency of micronucleated erythrocytes in peripheral blood of male and female mice. In summary, the toxicity of HDDC to rats and mice resulted from irritant properties of the chemical and was consistent with the effects of other irritant chemicals administered by inhalation. This toxicity was limited to the nose and airways. In the 2-week inhalation studies, deaths occurred in both rats and mice at the highest exposure level (800 mg/m(3)). In the 13-week studies, the no-observed-adverse-effect-level (NOAEL) for respiratory damage was 5 mg/m(3) for rats and mice. HDDC had no adverse effect on reproduction of either species and was not genotoxic. Synonyms: Hexamethylenediamine dihydrochloride; 1,6-diaminohexane dihydrochloride; 1,6-hexamethylenediamine dihydrochloride; 1,6- hexylenediamine dihydrochloride; 1,6-diamino-n-hexane dihydrochloride; HMDA; HDA; HDDC.
authors.forename: Charles
authors.initials: C
authors.lastname: Hebert