Tetrahydrofuran

Carcinogenicity

Description of key information

Tetrahydrofuran has been tested for carcinogenicity in chronic studies on rats and mice by the National Toxicology Program.  
 Critical target organs for neoplasia in these studies included the liver for mice, and kidney in male rats.  In exposed male mice, the incidences of hepatocellular tumours were not significantly different from the chamber controls.  The lower incidences of hepatocellular neoplasms in male mice at the 1800 ppm exposure concentration was attributed to the reduced survival of this group.  The incidences of combined hepatocellular neoplasms in male mice exposed to 200 ppm and in the chamber controls exceeded the historical control range for inhalation studies.  The incidence of combined hepatocellular neoplasms in male mice at the 600 ppm exposure concentration was at the upper limit of the historical control range.  Female mice exposed at 1800 ppm had significantly greater incidences of hepatocellular neoplasms than those of chamber controls and incidences increased with a positive trend.  In addition, the incidences of multiple hepatocellular neoplasms were increased in female mice exposed at 1800 ppm.  The incidences of combined hepatocellular neoplasms in female mice exposed to 1800 ppm exceeded the historical range for chamber controls in 2-year NTP inhalation studies.  Considering that THF is non-genotoxic, and that the hepatocellular tumours occurred at high, liver enzyme inducing doses, the liver tumours observed in this strain of mice are unlikely to be relevant to human cancer risk. 
 
In rats, Incidences of renal tubule epithelial adenoma were marginally increased in 600 and 1800 ppm males.  Female rats did not exhibit renal neoplasia.  The nature of these tumours was reviewed and concluded to be associated with age-related chronic progressive nephropathy, a physiological condition common in male rats and unlikely to be of relevance to human cancer risk.

Justification for classification or non-classification

Rat Kidney:

The consensus diagnoses of the PWG confirmed that there was no difference in the incidence of renal tubular proliferative changes (neoplastic and pre-neoplastic combined) when control and tetrahydrofuran-exposed groups were compared for the 2-year bioassay. Although the incidence of tubular adenomas was slightly higher in rats exposed to the 1800 ppm tetrahydrofuran, the difference was not statistically significant when compared with the control group, and there was no evidence of early tumor occurrence or of tumor progression to carcinoma. Furthermore, PWG members agreed that, based upon the absence of experimental results that would implicate genotoxic mechanisms for the observed proliferative changes, it was likely that atypical hyperplasias and adenomas in the control group resulted from regenerative processes associated with advanced CPN and/or low-grade alpha-2U-globulin nephropathy. In this connection, it was important to recognize that CPN in aging rats and alpha-2U-globulin nephropathy have no known human counterparts. Therefore, it was the consensus of the PWG that mechanisms that likely contributed to the formation of renal tubular adenomas in male rats assigned to the 2-year carcinogenesis bioassay with tetrahydrofuran (NTP Study No. 05181-03) pose no risk for humans.

Mouse Liver:

In female mice, the increased incidence of common hepatocellular tumors (adenoma and carcinoma) was most likely due toinduction of P450 enzymes and persistently increased zonal liver cell proliferation in zones 2 and 3. Given the negative results obtained in genotoxicity tests with tetrahydrofuran, and the lack of similar liver tumors in male mice or male or female rats, the liver tumors observed in female mice are presumed to be of little or no relevance for human hazard assessment.

Based on these findings, THF should not be rated for carcinogenicity. However there is a harmonsied classification for this substance as a Category 2 carcinogen under the EU CLP classification system (EC No 1272/2008), and this will be applied to the substance.

Additional information

CARCINOGENICITY

The carcinogenicity of tetrahydrofuran has been studied in 2-year inhalation toxicity and carcinogenicity studies in rats and mice. Groups of 50 male and female F344 rats were exposed to 0, 200, 600 or 1800 ppm of tetrahydrofuran by inhalation, 6 hours/day, 5 days/week for 105 weeks. No clinical findings related to tetrahydrofuran exposures were reported. Survival rates and mean body weights of male and female rats exposed to tetrahydrofuran were similar to chamber controls. There were neither significant gross pathological changes nor significant non-neoplastic changes noted in exposed rats. The incidence of renal tubule epithelial adenoma or carcinoma (combined) in exposed males occurred with a positive trend, and the incidence in 600 and 1800 ppm males exceeded the historical range for chamber controls in 2-year NTP inhalation studies. Based on the criteria of the NTP, there was some evidence for carcinogenicity in male F344/N rats. There was no evidence for carcinogenicity in female F344/N rats. Groups of 50 male and female B6C3F1 mice were exposed to 0, 200, 600 or 1800 ppm of tetrahydrofuran by inhalation, 6 hours/day, 5 days/week for 105 weeks. No clinical findings related to tetrahydrofuran exposures were reported for female mice. Male mice exposed at the highest test concentration were observed to be in a state of narcosis during and up to 1 hour after exposure. After week 36, the survival of male mice exposed at the highest exposure concentration (1800 ppm) was significantly less than that of the chamber controls. The highest level selected in the 2-year studies (1800 ppm) exceeded the maximum tolerated dose in male mice. Survival rates of female mice and mean body weights of male and female mice exposed to tetrahydrofuran were similar to chamber controls. The incidences and multiplicity of hepatocellular neoplasms were significantly greater in female mice exposed to 1800 ppm than in the chamber controls. The incidence of nephropathy in 200 ppm male mice was significantly greater than in chamber controls. Male mice exposed to 1800 ppm had significantly greater incidences of non-neoplastic lesions of the urogenital tract than did chamber controls. The incidences of inflammation of the penis and urethra and necrosis of the urethra in the 1800 ppm male mice were greater than those in the chamber controls. These may have been secondary effects of ascending urinary tract infection. Based on the criteria of the NTP, there was clear evidence for carcinogenicity in female B6C3F1 mice. There was no evidence for carcinogenicity in male B6C3F1 mice.

STUDIES RELATED TO THE MECHANISM OF TETRAHYDROFURAN CARCINOGENICITY

In a report from a Pathology Working Group (Bruner, 2009; see Section 7.12), a review of selected microscopic findings from male rats in the 2 -year carcinogenicity study confirmed that there was no difference in the incidence of renal tubular proliferative changes (neoplastic and pre-neoplastic combined) when control and tetrahydrofuran-exposed groups were compared. Although the incidence of tubular adenomas was slightly higher in rats exposed at 1800 ppm, the difference was not statistically significant when compared with the control group, and there was no evidence of early tumor occurrence or of tumor progression to carcinoma. At the highest exposure concentration in male rats (1800 ppm), the unequivocal concensus of the PWG was that two renal cell carcinomas observed by NTP pathologists were, in fact, benign adenomas rather than malignant tumors. Furthermore, PWG members agreed, based on the absence of experimental results implicating a genotoxic mechanism(s) for the observed proliferative changes, that it was most likely that atypical hyperplasias and adenomas in the control group resulted from a regernerative process associated with advanced chronic progressive nephropathy (CPN), and at the 1800 ppm exposure concentration, the proliferative changes resulted from either CPN or the associated alpha-2u-globulin nephropathy, which has no known counterpart in humans. It was the concensus of PWG members that the mechanisms that likely contributed to the formation of renal tubular adenomas in male rats assigned to the 2 -year carcinogenesis bioassay with tetrahydrofuran pose no risk for humans.

Male Fischer 344 rats were exposed by head-only inhalation exposures to tetrahydrofuran at concentrations of 0, 200, 600 or 1800 ppm (0, 600, 1800 or 5400 mg/m³) for up to 20 exposures (6 hours/day, 5 days/week). The results of this study indicate that in male rats, tetrahydrofuran induces alpha-2u globulin deposition in the cortex of kidneys accompanied by increased cell proliferation in cortical proximal tubules after exposure to concentrations of 1,800 and 5,400 mg/m³. These changes were accompanied by an increased apoptotic index. These effects in the target organ in male rats are considered to constitute the mechanisms of tumor formation. The No Observed Adverse Effect Concentration (NOAEC) under the condition of this study was 600 mg/L (200 ppm). In an accompanying study, female B6C3F1 mice were exposed by head-only to tetrahydrofuran at concentrations of 0, 200, 600 or 1800 ppm (0, 600, 1800 or 5400 mg/L) for up to 20 exposures (6 hours/day, 5 days/week). In the livers of female mice, induction of P450 enzymes and persistently increased zonal liver cell proliferation in zones 2 and 3 occurred after exposure to 5400 mg/m³. At 1,800 mg/m³, a transient increase in cell proliferation after 5 exposures was observed. These effects in female mice were considered to constitute the mechanisms of tumor formation.

The evaluation of cell proliferation (PCNA) in the kidney of male F 344/N rats and in the liver of female BGC3F1 mice after 13 weeks inhalation of tetrahydrofuran revealed no clear increase in cell replication that could be correlated to a tumorigenic mechanism. Beyond slight increases in the livers of mice at 1,800 ppm, there was a minimal decrease in the remaining dose groups. In the kidneys of the rats there was a minimal to slight decrease in all tubular compartments. No correlation could be established between the observed microscopic findings and the proliferation pattern. Based on the present study, the method used and after 13 weeks of application, it is not possible to give a definite answer to the question of contribution of cell proliferation to the tumorigenesis of Tetrahydrofuran.