NTP technical report on the toxicity studies of Glutaraldehyde (CAS No. 111-30-8) Adminstered by Inhalation to F344/N Rats and B6C3F1 Mice.

Glutaraldehyde is a potent sensory irritant with the capability to cross-link, or fix, proteins. It is used industrially as an antimicrobial agent and as a cold sterilant in hospitals, and it has a variety of other industrial uses. The toxicity of glutaraldehyde was evaluated in 2-week and 13-week inhalation exposure studies in F344/N rats and B6C3F1 mice. In addition to histopathology, evaluations included clinical pathology and assessments of sperm morphology and estrous cycle length. In vitro genetic toxicity studies included assessments of mutagenicity in Salmonella typhimurium and in mouse lymphoma L5178Y cells and analysis of chromosomal aberrations and sister chromatid exchanges in Chinese hamster ovary cells. The ability of glutaraldehyde to induce sex-linked recessive lethal mutations was also studied in vivo in Drosophila melanogaster. In 2-week inhalation studies, groups of five rats and five mice of each sex were exposed to glutaraldehyde by whole-body inhalation at concentrations of 0, 0.16, 0.5, 1.6, 5, and 16 ppm for 6 hours per day, 5 days per week. All rats and mice exposed to 5 or 16 ppm glutaraldehyde died before the end of the studies; all mice exposed to 1.6 ppm also died. Rats exposed to 1.6 ppm did not gain weight. Deaths were attributed to severe respiratory distress. Mice appeared to be more sensitive than rats because the small airways of the nasal passage of mice were more easily blocked by cell debris and keratin. Lesions noted in the nasal passage and larynx of rats and mice included necrosis, inflammation, and squamous metaplasia. At higher exposure concentrations, similar lesions were present in the trachea of rats and mice and in the lung and on the tongue of rats. In 13-week studies, groups of 10 rats and 10 mice of each sex were exposed to glutaraldehyde by whole-body inhalation at concentrations of 0, 62.5, 125, 250, 500, and 1000 ppb for 6 hours per day, 5 days per week. There were no exposure-related deaths in rats, but all mice exposed to 1000 ppb and two female mice exposed to 500 ppb died before the end of the study. Body weight gains were reduced in male rats exposed to 1000 ppb and in female rats exposed to 500 or 1000 ppb. Body weight gains of male mice exposed to 125, 250, or 500 ppb and female mice exposed to 250 or 500 ppb were reduced in a concentration-related manner. There was no clear evidence of systemic toxicity in rats or mice by histopathologic or clinical pathology assessments; however, exposure-related lesions in the respiratory tract were observed, and resembled those noted in the 2-week studies. In rats, the most severe lesions occurred in the anterior portions of the nasal passages and involved both the respiratory and olfactory epithelium. Hyperplasia and squamous metaplasia were most commonly noted on the lateral wall of the nasal cavity and on the tips of the nasoturbinates. Lesions were most extensive in rats exposed to 1000 ppb, but were also noted in the 250 and 500 ppb groups and in one male exposed to 125 ppb. In mice, histopathologic lesions in the respiratory tract were most severe in animals in the 1000 ppb group and consisted of minimal to mild squamous metaplasia of the laryngeal epithelium, suppurative inflammation in the anterior parts of the nasal cavity, and minimal squamous metaplasia on the tips of the nasoturbinates. Necrosis and inflammation were noted at lower concentrations, primarily in the anterior portion of the nasal passage. In genetic toxicity studies, glutaraldehyde was mutagenic with and without S9 metabolic activation in Salmonella typhimurium strains TA100, TA102, and TA104. Glutaraldehyde was mutagenic in mouse L5178Y lymphoma cells in the absence of S9 and induced sister chromatid exchanges in Chinese hamster ovary cells with and without S9. In one laboratory, chromosomal aberrations were induced in Chinese hamster ovary cells by glutaraldehyde in the absence of S9 only; no increase in chromosomal aberrations was observed with or without S9 in a second laboratory. Glutaraldehyde did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster treated as adults by feeding or injection or treated as larvae by feeding. In summary, exposure of rats and mice to glutaraldehyde by inhalation for up to 13 weeks resulted in a spectrum of necrotic, inflammatory, and regenerative lesions confined to the upper respiratory tract. Mice were somewhat more sensitive than rats because the small airways of the nasal passage in mice were more prone to blockage with cellular debris, bacteria, and keratin. The no-observed-adverse-effect level (NOAEL) was 125 ppb for respiratory lesions in rats. An NOAEL was not reached for mice, as inflammation was found in the anterior nasal passage at concentrations as low as 62.5 ppb. Synonyms: 1,5-Pentanedial; glutaral; glutaric dialdehyde; 1,3-diformylpropane.