National Toxicology Program

TR-382
Toxicology and Carcinogenesis Studies of Furfural (CASNo. 98-01-1) in F344/N Rats and B6C3F₁ Mice (Gavage Studies)

Chemical Formula: Chemical Formula: C5H4O2	-	3D Structure*
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Furfural is used as a precursor for the manufacture of furan, furfuryl alcohol,tetrahydrofuran, and their derivatives and as an industrial solvent. Furfuralis also present in numerous processed food and beverage products.Toxicologyand 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 sexfor16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted inSalmonella typhimurium, mouse lymphoma cells, Chinese hamsterovary(CHO) cells, Drosophila melanogaster, and mouse bone marrow cells.

Sixteen-Day Studies:

Rats received doses ranging from 15 to 240 mg/kg, andmice received doses from 25 to 400 mg/kg. Eight of 10 rats that received 240mg/kg died within 3 days. Final mean body weights of chemically exposedanimals were similar to those of vehicle controls; no compound-relatedhistologic lesions were observed in any dosed groups.

Thirteen-Week Studies:

Rats received doses ranging from 11 to 180 mg/kg,andmice received doses from 75 to 1,200 mg/kg. Most rats that received 180mg/kgdied; mean body weights of chemically exposed rats were similar to those ofvehicle controls. Mean relative and absolute liver and kidney weights wereincreased in male rats that received 90 mg/kg, and cytoplasmic vacuolizationofhepatocytes was increased in chemically exposed male rats.

Almost all mice that received doses of 600 or 1,200 mg/kg died within the first3 weeks. Mean body weights of chemically exposed mice were similar tothose ofvehicle controls throughout the studies. Mean absolute liver weights and liverweight to body weight ratios were increased in females that received 300mg/kg.Centrilobular coagulative necrosis and/or multifocal subchronic inflammationofthe liver were present in chemically exposed mice but not in vehicle controlmice.

Based on these results, doses selected for the 2-year studies were 0, 30, and60 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 ofchemically exposed and vehicle control animals were similar throughout thestudies for rats and mice. Two-year survival of male rats; low dose femalerats, and mice was unaffected by chemical exposure (male rats: vehiclecontrol, 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 highdose female rats was reduced by deaths associated with gavageadministration;the administration of furfural was considered to be a contributing factor inthese gavage-related deaths.

Nonneoplastic and Neoplastic Effects in the Two-Year Studies:

Centrilobularnecrosis of the liver occurred at increased incidences in chemically exposedmale rats (vehicle control, 3/50; low dose, 9/50; high dose, 12/50). Two highdose male rats had bile duct dysplasia with fibrosis, and two hadcholangiocarcinomas; neither lesion was seen in the other dose groups. Thehistorical incidence of bile duct neoplasms in corn oil vehicle control malerats is 3/2,145 (0.1%).

Multifocal pigmentation and chronic inflammation of the subserosa of the liveroccurred 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 ofhepatocellular adenomas and hepatocellular carcinomas in male mice andhepatocellular adenomas in female mice were significantly increased in thehighdose 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 exposedmalemice (0/50; 1/50; 1/49; 1/50), and a renal cortical adenoma was present in onelow dose female mouse; the historical incidence of renal cortical neoplasms inNational Toxicology Program 2-year corn oil gavage studies in male B6C3F₁miceis 8/2,183.

Forestomach hyperplasia occurred in chemically exposed female mice, andsquamous 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 inthepresence or absence of exogenous metabolic activation (S9) in onelaboratoryand an equivocal response was observed in TA100 in the absence of S9 in asecond laboratory. Exposure to furfural induced trifluorothymidine resistancein mouse L5178Y lymphoma cells in the absence of S9 (no evaluation wasmade inthe presence of S9), sister chromatid exchanges (SCEs) and chromosomalaberrations in CHO cells in the presence or absence of S9, and an increase insex-linked recessive lethal mutations but no reciprocal translocations in germcells of D. melanogaster; furfural did not induce SCEs or chromosomalaberrations in the bone marrow of B6C3F₁ mice.

Conclusions:

Under the conditions of these 2-year gavage studies, there wassome evidence of carcinogenic activity of furfural for male F344/N ratsbased on the occurrence of uncommon cholangiocarcinomas in two animalsand bileduct dysplasia with fibrosis in two other animals. There was no evidence ofcarcinogenic activity for female F344/N rats that received doses of 0, 30,or 60 mg/kg furfural. There was clear evidence of carcinogenic activityfor male B6C3F₁ mice, based on increased incidences of hepatocellularadenomasand hepatocellular carcinomas. There was some evidence of carcinogenicactivity in female B6C3F₁ mice, based on increased incidences ofhepatocellular adenomas. Renal cortical adenomas or carcinomas in malemiceand squamous cell papillomas of the forestomach in female mice may havebeenrelated to exposure to furfural.

Synonyms: 2-furancarboxaldehyde; 2-furaldehyde; pyromucic aldehyde

Common Name: Artificial oil of ants

Report Date: March 1990

Pathology Tables, Survival and Growth Curves from NTP 2-year Studies

Target Organs & Incidences from 2-year Studies

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