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https://ntp.niehs.nih.gov/go/tox078abs

Abstract for TOX-78

Toxicity Studies of Triethylamine Administered by Inhalation to F344/N Rats and B6C3F1/N Mice

CASRN: 121-44-8
Chemical Formula: C6H15N
Molecular Weight: 101.19
Synonyms/Common Names: (Diethylamino) ethane; ethanamine, N,N-diethyl- (9CI); N,N-diethylethanamine; triethyl-(diethylamino) ethaneamine
Report Date: March 2018

FULL REPORT PDF

Abstract

Triethylamine is used primarily as a catalyst to cure the resin systems incorporated into sand cores for foundry molds. It is also used as a curing catalyst in phenol-formaldehyde particle board adhesives, for the precipitation and purification of penicillin and cephalosporin antibiotics, and in the interfacial polymerization process for the production of polycarbonate resins. Triethylamine was nominated by the United Auto Workers Union for long-term toxicity and carcinogenicity studies based on its high production volume, the large number of occupationally exposed workers, and the lack of carcinogenicity data. Male and female F344/N rats and B6C3F1/N mice were exposed to triethylamine (greater than 99% pure) by whole body inhalation for 2 weeks or 3 months. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes.

In the 2-week toxicity studies, groups of five male and five female F344/N rats and B6C3F1/N mice were exposed to triethylamine at concentrations of 0, 100, 200, 400, 800, or 1,000 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 16 (rats) or 17 (mice) days. All rats exposed to 800 or 1,000 ppm died after exposure on day 1; all mice exposed to 800 or 1,000 ppm died between day 1 (postexposure) and day 11. The final mean body weights of all surviving groups of exposed male rats and 200 and 400 ppm female rats were significantly less than those of the chamber controls. In mice, the final mean body weights of 400 ppm males and females were significantly less than those of the chamber controls. Possible chemical-related clinical findings in 400 ppm rats and mice included lethargy, abnormal breathing, ataxia, tremor, nasal discharge (rats), and thinness (mice). Kidney weights of 100 ppm female rats were significantly greater than those of the chamber controls.

In the nose of male rats, there were significantly increased incidences of respiratory epithelium hyperplasia in all surviving exposed groups; significantly increased incidences of suppurative inflammation in the 200 and 400 ppm groups; significantly increased incidences of turbinate necrosis, squamous metaplasia of the respiratory epithelium, and respiratory epithelium ulcer in the 400 ppm group; and a significantly increased incidence of olfactory epithelium atrophy in the 200 ppm group. In the nose of female rats, there were significantly increased incidences of suppurative inflammation, squamous metaplasia of the respiratory epithelium, and respiratory epithelium ulcer in the 400 ppm group; significantly increased incidences of respiratory epithelium hyperplasia in the 100 and 200 ppm groups; and a significantly increased incidence of olfactory epithelium atrophy in the 200 ppm group.

All rats that died early had necrosis of the respiratory epithelium of the nose and necrosis of the bronchus. In the lung of surviving groups of male and female rats, there were significantly increased incidences of bronchus degeneration in the 200 and 400 ppm groups and significantly increased incidences of suppurative inflammation and regeneration of the bronchus in the 400 ppm groups. Rats dying early often showed corneal degeneration or necrosis, and a few rats in the 100 and 200 ppm groups exhibited subepithelial vesicles of the cornea.

Turbinate necrosis occurred in the nose of all exposed mice except the 100 ppm groups. There were significantly increased incidences of olfactory epithelium atrophy in the nose of all surviving groups of exposed mice, and significantly increased incidences of acute inflammation and squamous metaplasia of the respiratory epithelium in 200 and 400 ppm mice.

Lung lesions observed only in the groups with early mortality included necrosis of the bronchus in male and female mice and cytoplasmic vacuolization of the bronchus in females. In 400 ppm mice, incidences of chronic active inflammation of the bronchus were increased. Groups of mice with early mortality also had corneal necrosis and cataracts.

In the 3-month toxicity studies, groups of 10 male and 10 female F344/N rats and B6C3F1/N mice were exposed to triethylamine at concentrations of 0, 12.5, 25, 50, 100, or 200 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. All exposed rats and mice survived to the end of the studies. Body weights of 200 ppm rats and mice were significantly less than those of the chamber controls. In male rats, differences in reproductive parameters included decreased spermatozoa motility at 50 ppm or greater and increased spermatid heads per mg testis in the 100 and 200 ppm groups.

In the olfactory epithelium of the nose of rats, there were significantly increased incidences of atrophy in males exposed to 50 ppm or greater and in females exposed to 25 ppm or greater. In the respiratory epithelium of the nose of rats, there were significantly increased incidences of hyperplasia in males and females exposed to 25 ppm or greater. In the lung of female rats, there were significantly increased incidences of histiocyte cellular infiltration of the alveolus in the 100 and 200 ppm groups. Corneal lesions of the eye were noted in four males and six females exposed to 200 ppm.

In the olfactory epithelium of the nose of mice, there were significantly increased incidences of atrophy in males and females exposed to 50 ppm or greater and significantly increased incidences of cytoplasmic vacuolization in 50 ppm males and females. In the respiratory epithelium of the nose of mice, there were significantly increased incidences of squamous metaplasia in 200 ppm males and females. There were significantly increased incidences of turbinate hyperostosis in all exposed groups of male and female mice and significantly increased incidences of turbinate necrosis in 200 ppm males and females.

Triethylamine was not mutagenic in any of four strains of S. typhimurium, with or without exogenous metabolic activation. An equivocal increase, based on a trend test analysis, in the frequency of micronucleated erythrocytes was observed in peripheral blood of male mice sampled at the end of the 3-month study; no increase in micronucleated erythrocytes was seen in female mice.

Under the conditions of the 3-month inhalation studies, there were treatment-related lesions in male and female rats and mice. The major targets of triethylamine exposure in rats and mice included the nose and eyes. In rats, the most sensitive measure of triethylamine exposure was respiratory epithelium hyperplasia of the nasal cavity with a lowest-observed-effect level (LOEL) of 12.5 ppm in males and females. In mice, the most sensitive measure of triethylamine exposure was turbinate hyperostosis of the nasal cavity with a LOEL of 12.5 ppm in males and females.

National Toxicology Program (NTP). 2018. NTP technical report on the toxicity studies of triethylamine (CASRN 121-44-8) administered by inhalation to F344/N rats and B6C3F1/N mice. Research Triangle Park, NC: National Toxicology Program. Toxicity Report 78. https://doi.org/10.22427/NTP-TOX-78

Studies

Summary of Findings Considered to be Toxicologically Relevant in Rats and Mice Exposed to Triethylamine for 3 Months by Inhalation
  Male
F344/N Rats
Female
F344/N Rats
Male
B6C3F1/N Mice
Female
B6C3F1/N Mice
Exposure concentrations 0, 12.5, 25, 50, 100, 200 ppm 0, 12.5, 25, 50, 100, 200 ppm 0, 12.5, 25, 50, 100, 200 ppm 0, 12.5, 25, 50, 100, 200 ppm
Survival rates 10/10, 10/10, 10/10, 10/10, 10/10, 10/10 10/10, 10/10, 10/10, 10/10, 10/10, 10/10 10/10, 10/10, 10/10, 10/10, 10/10, 10/10 10/10, 10/10, 10/10, 10/10, 10/10, 10/10
Body weights 200 ppm group 13% less than the chamber control group 200 ppm group 13% less than the chamber control group 200 ppm group 15% less than the chamber control group 200 ppm group 11% less than the chamber control group
Clinical observations No effect observed No effect observed No effect observed No effect observed
Organ weights No effect observed No effect observed No effect observed No effect observed
Clinical pathology No effect observed No effect observed No effect observed (hematology only) No effect observed (hematology only)
Reproductive effects Sperm motility decreased No effect observed No effect observed No effect observed
Nonneoplastic effects Nose: respiratory epithelium, hyperplasia (0/10, 3/10, 9/10, 9/10, 10/10, 10/10); olfactory epithelium, atrophy (0/10, 0/10, 0/10, 10/10, 10/10, 10/10)
Eye: cornea, mineralization (0/9, 0/10, 0/10, 0/10, 1/10, 3/10); cornea, epithelium, vacuolation (0/9, 0/10, 0/10, 0/10, 0/10, 2/10); cornea, necrosis (0/9, 0/10, 0/10, 0/10, 0/10, 1/10)
Nose: respiratory epithelium, hyperplasia (0/10, 3/10, 9/10, 10/10, 10/10, 10/10); olfactory epithelium, atrophy (0/10, 0/10, 4/10, 10/10, 10/10, 10/10)
Eye: cornea, mineralization (0/10, 0/10, 0/10, 0/10, 0/10, 2/10); cornea, vesicle, subepithelial (0/10, 0/10, 0/10, 0/10, 0/10, 3/10); cornea, necrosis (0/10, 0/10, 0/10, 0/10, 0/10, 1/10)
Nose: turbinate, hyperostosis (0/10, 10/10, 9/10, 10/10, 10/10, 10/10); olfactory epithelium, atrophy (0/10, 0/10, 0/10, 9/10, 10/10, 10/10) Nose: turbinate, hyperostosis (0/10, 8/10, 10/10, 10/10, 9/10, 10/10); olfactory epithelium, atrophy (0/10, 0/10, 0/10, 10/10, 10/10, 10/10)
Genetic Toxicology
Assay Results
Bacterial gene mutations (in vitro):
 
Negative in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 with and without exogenous metabolic activation
Micronucleated reticulocytes (in vivo):
Mouse

Equivocal in males and negative in females