Registration Dossier

Administrative data

Description of key information

Repeated-dose drinking water toxicity studies in rats indicate tetrahydrofuran is of low toxicity.  The subacute and subchronic toxicity of tetrahydrofuran in rats and mice is generally moderate to low following repeated-dose inhalation exposures.  Mice are more sensitive than rats following repeated inhalation exposures.

Key value for chemical safety assessment

Additional information

Oral

The repeated-dose oral toxicity of tetrahydrofuran has been studied in the rat. In a key study, male and female rats were administered tetrahydrofuran in drinking water for 4 weeks at concentrations of 0, 1.0, 10, 100 or 1000 mg/l. At the highest concentration, this resulted in a maximum intake of 113.3 mg/kg bwt/day (females). There were no significant biochemical or hematological changes noted. Minimal pathological changes were noted in the thyroid, liver and kidneys. In the thyroid, changes consisted of increased epithelial heights, reduced colloid density and angular collapse of follicles. In the liver, changes consisted of mild increases in perivenous cytoplasmic homogeneity and periportal cytoplasmic density. In the kidney, tubular changes consisted of eosinophilic inclusions, pyknosis, and central displacement of nuclei. Treatment related morphological changes were considered mild and adaptive in nature and were not related to any functional or biochemical changes.

Dermal

No repeated-dose dermal toxicity studies were identified for tetrahydrofuran.

Inhalation

The subacute and subchronic repeated-dose inhalation toxicity of tetrahydrofuran has been studied in rats and mice. Male and female F344/N rats were exposed to 0, 66, 200, 600, 1800 or 5000 ppm tetrahydrofuran by inhalation, 6 hours/day, 5 days/week, for 14 weeks. All rats survived these exposures. Immediately following exposures, rats in the 5000 ppm exposure group exhibited ataxia. Hematologic and serum changes were minimal, with most values falling within physiologic ranges. Absolute and relative thymus and spleen weights of male and female rats were significantly less than those of chamber controls but were not associated with appreciable histologic changes. Effects seen in the thymus and spleen may have been caused by stress associated with test article administration. Absolute and relative liver weights of female rats at the 5000 ppm exposure concentration were significantly greater than chamber controls. Increased incidences of minimal to mild hyperplasia of the forestomach were observed in male and female rats exposed to 5000 ppm. Minimal suppurative inflammation was associated with forestomach hyperplasia in two male and four female rats exposed to 5000 ppm. Male and female B6C3F1 mice were exposed to 0, 66, 200, 600, 1800 or 5000 ppm tetrahydrofuran by inhalation, 6 hours/day, 5 days/week, for 14 weeks. Three male mice at the highest dose level died or were killed in a moribund state prior to study termination. All female mice survived until study termination. Mean final body weights and body weight gains of all exposed groups of male mice were similar to those of the chamber controls. Final mean body weights or body weight gains of 5000 ppm female mice were significantly greater than those of the chamber controls. Male and female mice at the 1800 and 5000 ppm exposure concentrations were observed to be in a state of narcosis (described by stupor) during exposure periods. Mice exposed to 1800 ppm were fully awake and alert immediately after exposure; however, mice exposed to 5000 ppm required up to 2 hours for recovery. Absolute and relative liver weights of male mice exposed to 600 ppm or greater and of female mice exposed to 1800 ppm or 5000 ppm were significantly greater than those of the chamber controls. Absolute and relative lung and heart weights of female mice exposed to 5000 ppm were significantly less than those of chamber controls. Absolute and relative thymus weights of male mice exposed to 600, 1800, or 5000 ppm were significantly less than those of the chamber controls. Absolute and relative spleen weights of male and female mice exposed to 5000 ppm were significantly less than those of the chamber controls. Although there were decreases in thymus and spleen weights, corresponding histopathologic changes were not readily apparent. However, the spleens of male and female mice exposed to 5000 ppm had smaller cross sections. The significance of the organ weight differences is not clear, but the differences may be due to stress associated with tetrahydrofuran administration. The adrenal glands of all female mice exposed to 5000 ppm had mild degeneration of the X-zone of the innermost cortex. Uterine atrophy was observed in all female mice exposed at 5000 ppm.

The neurotoxic potential of tetrahydrafuran was determined in a subchronic exposures of adults rats to atmospheres containing 0, 500, 1500 or 3000 ppm of the test compound for 6 hours/day, 5 days/week for at least 90 days (see Section 7.9.1). Neurobehavioral studies and neuropathology were obtained in this study. A compound-related sedation, although transient, was regarded as an adverse toxicological effect. There were no biologically relevant, compound-related effects on body weight or body weight gains at any exposure concentration. There were no other biologically relevant, compound-related effects observed during clinical observations nor were any significant neuropathological changes noted.

In a subacute study in rats, 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) (see Section 7.9.3 of this document). The results of this study indicate that in male rats, tetrahydrofuran induces alpha-2u globulin deposition in the cortex of the 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. Histopathological analysis of the kidneys revealed no treatment-related effects. In a subacute inhalation study in mice, 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) (see Section 7.9.3 of this document). 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. No significant gross or histopathological lesions were noted in mice as a result of inhalation exposures.

The chronic repeated-dose inhalation toxicity of tetrahydrofuran has been studied in rats and mice in 2-year toxicity and carcinogenicity studies. 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 (see Section 7.7). No clinical findings related to tetrahydrofuran exposures were reported. Survival rates and mean body weights of male and female rats were similar to chamber controls. There were neither significant gross pathological changes nor significant non-neoplastic changes noted in exposed rats. 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 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 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 latter effects may have been secondary effects of an ascending urinary tract infection.

Justification for classification or non-classification

At moderate to low exposure levels, severe lesions are generally absent in repeated-dose toxicity studies with tetrahydrofuran conducted in rats and mice following either oral or inhalation exposures. Chronic inhalation toxicity studies in rats and mice are most appropriate for determining the need for classification based on repeated or prolonged exposures or based on the occurence of specific target organ effects. In 2 -year inhalation toxicity studies in rats, there were no significant non-neoplastic changes noted at exposure concentrations as high as 1800 ppm (5.3 mg/L). In 2 -year chronic inhalation toxicity studies in mice, the lowest exposure concentration causing a specific target organ effect was 200 ppm (0.6 mg/L). Nephropathy in male mice that was significantly greater than in the chamber controls was present at this exposure concentration. Based on a guidance level of </= 0.25 mg/L (referring to 6 hour/day inhalation exposures of rats in a 90 -day study), the 0.6 mg/L level would not result in a R48 (Danger of serious damage to health by prolonged exposure) classification under the EU DSD classification system (EU Directive 67/548/EEC). The guidance proposed under the EU CLP (EU Regulation 1272/2008) classification sytem indicates a range of 0.2 -1.0 mg/L (referring to 6 hour/day inhalation exposures of rats in a 90 -day study) for a Categroy 2 classification (Specific Target Organ Toxicity). Although the effect concentration of 0.6 mg/L derived from chronic exposures in mice falls within this range, subchronic (14 -week) exposures in mice indicated no histopathologically relevant organ changes in mice at concentrations as high as 1800 ppm (5.3 mg/L). Thus, no classification is required for Specific Target Organ Toxicity, repeated exposure, under the EU CLP classification system.