Toxicology and Carcinogenesis Studies of Furfuryl Alcohol (CAS No. 98-00-0) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).
Furfuryl alcohol-based resins are used as binding agents in foundry sand and as corrosion inhibitors in mortar, grout, and cement. Because of their heat resistance, furan resins are used in the manufacture of fiberglass-reinforced plastic equipment. Furfuryl alcohol was selected for evaluation because of the absence of data on its carcinogenic potential and its large production volume, widespread use in manufacturing, and ubiquitous presence in consumer goods. Male and female F344/N rats and B6C3F1 mice were exposed to furfuryl alcohol (greater than 98% pure) by inhalation for 16 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse bone marrow cells. 16-DAY STUDY IN RATS: Groups of five male and five female rats were exposed to concentrations of 0, 16, 31, 63, 125, or 250 ppm furfuryl alcohol by inhalation, 6 hours per day, 5 days per week for 16 days. All male and female rats exposed to 250 ppm died by day 2 of the study, and one male rat exposed to 125 ppm died on day 5. Final mean body weights of male and female rats exposed to 125 ppm were significantly less than those of the chamber control groups. Male rats exposed to 31, 63, or 125 ppm and female rats exposed to 125 ppm gained less weight than the chamber control groups. Clinical findings included dyspnea, hypoactivity, and nasal and ocular discharge in males and females exposed to 63, 125, or 250 ppm. All exposed animals developed lesions in the nasal respiratory epithelium and olfactory epithelium, and the severities of these lesions generally increased with increasing exposure concentration. 16-DAY STUDY IN MICE: Groups of five male and five female mice were exposed to concentrations of 0, 16, 31, 63, 125, or 250 ppm furfuryl alcohol by inhalation, 6 hours per day, 5 days per week for 16 days. All male and female mice exposed to 250 ppm died by day 4 of the study, and one female mouse exposed to 125 ppm died on day 14. Mean body weights of male and female mice exposed to 63 or 125 ppm were significantly less than those of the chamber control groups. All exposed animals except one 16 ppm male developed lesions in the nasal respiratory epithelium and/or olfactory epithelium, and the severities of these lesions generally increased with increasing exposure concentration. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to furfuryl alcohol at concentrations of 0, 2, 4, 8, 16, or 32 ppm, 6 hours per day, 5 days per week for 14 weeks. All rats survived to the end of the study. The mean body weight gain of females exposed to 32 ppm was less than that of the chamber control group. Exposure-related increases in the incidences of squamous metaplasia of the respiratory and transitional epithelium, goblet cell hyperplasia of the respiratory epithelium, and hypertrophy of the respiratory epithelium lining the nasopharyngeal duct were observed in the nose of male and female rats. The incidences of degeneration, hyperplasia, metaplasia, and surface exudate of the olfactory epithelium generally increased with increasing exposure concentration in males and females. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to furfuryl alcohol at concentrations of 0, 2, 4, 8, 16, or 32 ppm, 6 hours per day, 5 days per week for 14 weeks. All mice survived to the end of the study. Heart weights of 32 ppm males were significantly less than those of the chamber controls. Exposure-related histologic changes included degeneration, metaplasia, and chronic inflammation of the olfactory epithelium; hyaline droplets of the respiratory epithelium; and squamous metaplasia of the submucosal gland of the cuboidal epithelium in males and females. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to furfuryl alcohol by inhalation, 6 hours per day, 5 days per week for 105 weeks, at concentrations of 0, 2, 8, or 32 ppm. Survival and Body Weights All male rats exposed to 32 ppm died by week 99; survival of all other exposed groups of male and femald female rats was similar to that of the chamber control groups. Mean body weights of 32 ppm males were less than those of the chamber control group beginning at week 19. Pathology Findings All groups of exposed male and female rats had significantly increased incidences of nonneoplastic histologic changes of the nose compared to the chamber control groups. An adenoma of the lateral wall of the nose was observed in one 2 ppm male and one 8 ppm female, an adenoma of the respiratory epithelium was observed in one 8 ppm male and one 32 ppm female, one carcinoma of the respiratory epithelium was observed in a 32 ppm male, and squamous cell carcinomas of the nose were observed in three 32 ppm males. Renal tubule adenomas were present in one chamber control male, one 2 ppm male, two 8 ppm males, and two 32 ppm females. One 2 ppm female had a renal tubule carcinoma. Additional histologic sections from the kidney revealed the presence of additional hyperplasias in all groups of males and females; one additional renal tubule adenoma was observed in each of the chamber control, 2 ppm, and 8 ppm male groups, and four additional adenomas were observed in 32 ppm males. In females, two additional adenomas were found in the 8 ppm group, one adenoma in the 32 ppm group, and one carcinoma in the 2 ppm group. The severities of nephropathy relative to the chamber controls were increased in 32 ppm males and females. Males exposed to 32 ppm had extrarenal signs indicative of marked nephropathy including parathyroid gland hyperplasia and fibrous osteodystrophy. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to furfuryl alcohol by inhalation, 6 hours per day, 5 days per week for 105 weeks, at concentrations of 0, 2, 8, or 32 ppm. Survival, Body Weights, and Clinical Findings Survival of exposed males and females was similar to that of the chamber control groups. Mean body weights of exposed males were generally similar to those of the chamber control group throughout the study. Mean body weights of exposed females were less than those of the chamber control group during year 2 of the study. Female mice exposed to 32 ppm developed focal corneal opacities. Pathology Findings The incidences of renal tubule neoplasms were increased in 32 ppm male mice compared to the chamber control group and exceeded the historical control range for inhalation studies. Step sectioning revealed the presence of additional hyperplasias in the chamber control and exposed groups and one adenoma in 32 ppm males. The severity of nephropathy increased with increasing exposure concentration in male mice. The incidence of renal tubule degeneration in male mice exposed to 32 ppm was significantly greater than in the chamber control group. Incidences of a variety of nonneoplastic lesions of the nose were significantly greater in all exposed groups of male and female mice than in the chamber control groups. The incidence of degeneration of the cornea was significantly greater in 32 ppm female mice compared to the chamber control group. GENETIC TOXICOLOGY: Furfuryl alcohol was not mutagenic in Salmonella typhimurium strain TA98, TA100, TA1535, or TA1537, with or without S9. It did induce sister chromatid exchanges in cultured Chinese hamster ovary cells in the absence of S9, but not in the presence of S9. No induction of chromosomal aberrations was noted in cultured Chinese hamster ovary cells treated with furfuryl alcohol in the absence of S9, but in the presence of S9 an equivocal result was obtained. In vivo, no induction of sister chromatid exchanges, chromosomal aberrations, or micronuclei was noted in bone marrow cells of male mice after treatment with furfuryl alcohol. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was some evidence of carcinogenic activity of furfuryl alcohol in male F344/N rats based on increased incidences of combined neoplasms of the nose. There was equivocal evidence of carcinogenic activity of furfuryl alcohol in female F344/N rats based on marginally increased incidences of neoplasms of the nose and renal tubule neoplasms. There was some evidence of carcinogenic activity of furfuryl alcohol in male B6C3F1 mice based on increased inci dences of renal tubule neoplasms. There was no evidence of carcinogenic activity of furfuryl alcohol in female B6C3F1 mice exposed to 2, 8, or 32 ppm. Exposure of male and female rats and male mice to furfuryl alcohol was associated with increased incidences of nonneoplastic lesions of the nose and increased severities of nephropathy. Exposure of female mice to furfuryl alcohol was associated with increased incidences of nonneoplastic lesions of the nose and corneal degeneration. Synonyms: 2-Furancarbinol; 2-furanmethanol, furfuralcohol, a-furylcarbinol; 2-hydroxymethylfuran