title: NTP Toxicology and Carcinogenesis Studies of Furfural (CAS No. 98-01-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
abstract: Furfural is used as a precursor for the manufacture of furan, furfuryl alcohol, tetrahydrofuran, and their derivatives and as an industrial solvent. Furfural is also present in numerous processed food and beverage products. NTP Toxicology and Carcinogenesis studies were conducted by administering furfural (99% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, Chinese hamster ovary (CHO) cells, Drosophila melanogaster, and mouse bone marrow cells. Sixteen-Day Studies: Rats received doses ranging from 15 to 240 mg/kg, and mice received doses from 25 to 400 mg/kg. Eight of 10 rats that received 240 mg/kg died within 3 days. Final mean body weights of chemically exposed animals were similar to those of vehicle controls; no compound-related histologic lesions were observed in any dosed groups. Thirteen-Week Studies: Rats received doses ranging from 11 to 180 mg/kg, and mice received doses from 75 to 1,200 mg/kg. Most rats that received 180 mg/kg died; mean body weights of chemically exposed rats were similar to those of vehicle controls. Mean relative and absolute liver and kidney weights were increased in male rats that received 90 mg/kg, and cytoplasmic vacuolization of hepatocytes was increased in chemically exposed male rats. Almost all mice that received doses of 600 or 1,200 mg/kg died within the first 3 weeks. Mean body weights of chemically exposed mice were similar to those of vehicle controls throughout the studies. Mean absolute liver weights and liver weight to body weight ratios were increased in females that received 300 mg/kg. Centrilobular coagulative necrosis and/or multifocal subchronic inflammation of the liver were present in chemically exposed mice but not in vehicle control mice. Based on these results, doses selected for the 2-year studies were 0, 30, and 60 mg/kg for rats and 0, 50, 100, and 175 mg/kg for mice. Body Weight and Survival in the Two-Year Studies: Mean body weights of chemically exposed and vehicle control animals were similar throughout the studies for rats and mice. Two-year survival of male rats; low dose female rats, and mice was unaffected by chemical exposure (male rats: vehicle control, 31/50; low dose, 28/50; high dose, 24/50; female rats: 28/50; 32/50; 18/50; male mice: vehicle control, 35/50; low dose, 28/50; mid dose, 24/50; high dose, 27/50; female mice: 33/50; 28/50; 29/50; 32/50). Survival of high dose female rats was reduced by deaths associated with gavage administration; the administration of furfural was considered to be a contributing factor in these gavage-related deaths. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Centrilobular necrosis of the liver occurred at increased incidences in chemically exposed male rats (vehicle control, 3/50; low dose, 9/50; high dose, 12/50). Two high dose male rats had bile duct dysplasia with fibrosis, and two had cholangiocarcinomas; neither lesion was seen in the other dose groups. The historical incidence of bile duct neoplasms in corn oil vehicle control male rats is 3/2,145 (0.1%). Multifocal pigmentation and chronic inflammation of the subserosa of the liver occurred in chemically exposed mice (pigmentation--male: 0/50; 0/50; 8/49; 18/50; female: 0/50; 0/50; 0/50; 11/50; chronic inflammation--male: 0/50; 0/50; 8/49; 18/50; female: 0/50; 0/50; 1/50; 8/50). The incidences of hepatocellular adenomas and hepatocellular carcinomas in male mice and hepatocellular adenomas in female mice were significantly increased in the high dose group compared with those in the vehicle controls (male--adenomas: 9/50; 13/50; 11/49; 19/50; carcinomas: 7/50; 12/50; 6/49; 21/50; female--adenomas: 1/50; 3/50; 5/50; 8/50; adenomas or carcinomas, combined: 5/50; 3/50; 7/50; 12/50). Three renal cortical adenomas or carcinomas occurred in chemically exposed male mice (0/50; 1/50; 1/49; 1/50), and a renal cortical adenoma was present in one low dose female mouse; the historical incidence oal incidence of renal cortical neoplasms in National Toxicology Program 2-year corn oil gavage studies in male B6C3F1 mice is 8/2,183. Forestomach hyperplasia occurred in chemically exposed female mice, and squamous cell papillomas were increased in high dose female mice (hyperplasia: 0/50; 5/50; 5/50; 3/50; papillomas: 1/50; 0/50; 1/50; 6/50). Genetic Toxicology: In gene mutation tests with four strains of Salmonella (TA98, TA100, TA1535, and TA1537), no mutagenic activity was observed in the presence or absence of exogenous metabolic activation (S9) in one laboratory and an equivocal response was observed in TA100 in the absence of S9 in a second laboratory. Exposure to furfural induced trifluorothymidine resistance in mouse L5178Y lymphoma cells in the absence of S9 (no evaluation was made in the presence of S9), sister chromatid exchanges (SCEs) and chromosomal aberrations in CHO cells in the presence or absence of S9, and an increase in sex-linked recessive lethal mutations but no reciprocal translocations in germ cells of D. melanogaster; furfural did not induce SCEs or chromosomal aberrations in the bone marrow of B6C3F1 mice. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of furfural for male F344/N rats based on the occurrence of uncommon cholangiocarcinomas in two animals and bile duct dysplasia with fibrosis in two other animals. There was no evidence of carcinogenic activity for female F344/N rats that received doses of 0, 30, or 60 mg/kg furfural. There was clear evidence of carcinogenic activity for male B6C3F1 mice, based on increased incidences of hepatocellular adenomas and hepatocellular carcinomas. There was some evidence of carcinogenic activity in female B6C3F1 mice, based on increased incidences of hepatocellular adenomas. Renal cortical adenomas or carcinomas in male mice and squamous cell papillomas of the forestomach in female mice may have been related to exposure to furfural. Synonyms: 2-furancarboxaldehyde; 2-furaldehyde; pyromucic aldehyde Common Name: Artificial oil of ants