Tetrahydrofuran

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Subchronic and chronic inhalation toxicity studies in rats and mice have been conducted with full histopathological analysis of reproductive organs.

Additional information

REPRODUCTIVE TOXICITY

The reproductive toxicity of tetrahydrofuran (THF) has been studied in rats following drinking water administration. In a one-generation range-finding reproductive and developmental toxicity study following OECD Guideline 415, the administration of THF in drinking water to male and female Wistar rats resulted in dose-related, statistically significant reductions in water consumption at all dose levels [4,000 (455 mg/kg), 8,000 (797 mg/kg), or 12,000 ppm (1098 mg/kg)] in parental animals (both sexes), a diminished food intake in high-dose parental males and increased relative kidney weights at 12,000 ppm in both sexes and at 8,000 ppm in parental females. The test substance administrated up to 12000 ppm caused no treatment-related changes in hematology, clinical chemistry or urine parameters nor any treatment-related gross lesions. There were no indications of a treatment-related impairment of the reproductive function of the F0 parental rats at dose levels up to and including the highest dose level. The NOAEL for parental animals (P) in the one-generation study was reported as < 4000 ppm (the lowest dose level tested). In a follow-up definitive two-generation reproductive and developmental toxicity study following OECD Guideline 416, THF was administered in the drinking water at 0, 1000, 3000 or 9000 ppm to male and female Wistar rats. Clear signs of general toxicity were noted at the highest dose level (9,000 ppm) and consisted of statistically significantly reduced water intake in F0 and F1 parents throughout the different study phases. Reductions in water consumption may have accounted, in part, for reduced food consumption and reduced body weight/body weight gains. Slight but sometimes statistically significant reductions in water consumption were also seen in the 3,000 ppm F0 parental animals and F1 dams during lactation. Body weights of the F0 parental rats were statistically significantly reduced during the first premating weeks, in F0 females during gestation and lactation, and in F1 males throughout the study period. Slight impairments in body weight gain were only observed in high dose F1 males. Mean absolute and/or relative kidney weights of the males and females in the high dose group were significantly increased. These increases were considered treatment related although no morphological correlates were detected to account for the increases. No gross or microscopic lesions were noted in either male or female rats of the F0 or F1 generation parental animals. There were no indications from clinical examinations that THF administration caused any adverse effects on reproductive parameters of the parental animals. The reduced mean number of F2 pups delivered by F1 dams at the highest dose, although lower than control or the historical control range, was considered spontaneous in nature and not compound related. Statistically significant impairments in body weight/body weight gains were observed in F1 and F2 pups. The only signs of developmental toxicity were noted in F2 pups and consisted of delayed auditory canal opening and eye opening. The NOAEL for reproductive effects in the two-generation study was reported as 9,000 ppm based on a lack of significant adverse effects. The NOAEL for toxicity in F0 and F1 parental animals was reported as 3000 ppm based on effects on food and water consumption and on body weight and body weight gains. In the two generation study, mean intakes of THF in F0 and F1 parental males were 714 and 787 mg/kg bwt/day, respectively, at the 9000 ppm exposure concentration. For F0 and F1 females, mean intakes of THF varied from 742 to 1365 mg/kg bwt/day, depending on study phase, at the 9000 ppm exposure concentration.

Short description of key information:
The reproductive and developmental toxicity of THF were studied in both one-generation and two-generation studies in rats following drinking water administration.

Effects on developmental toxicity

Description of key information

The developmental toxicity of THF has been studied in both rats and mice following inhalation exposures.  Developmental effects were also assessed in a two-generation reproductive and developmental toxicity studies in rats following drinking water administration.

Additional information

DEVELOPMENTAL TOXICITY

The developmental toxicity/teratogenicity of tetrahydrofuran has been studied in both rats and mice following inhalation exposures. Pregnant and virgin female Sprague-Dawley rats were exposed to 0, 600, 1800 or 5000 ppm of tetrahydrofuran vapors whole-body for 6 hours/day, 7 days/week on days of gestation (DG) 6 to 19. Pregnant rats at the 5000 ppm exposure concentration displayed decreased body weights, however, virgin female rats were not similarly affected indicating that pregnancy was a factor in the toxicological response. Mean gravid uterine weights and extra-gestational weight gains were reduced at the 5000 ppm exposure concentration relative to the control, but the differences were not significant. There were no effects on the percentage of live rat fetuses/litter or on fetal sex ratios. Fetal body weights were reduced at the highest exposure concentration. Significant fetal malformations were not observed, but several malformations were observed at low incidences (< 0.4% in all cases) that were not present in either the concurrent control or contemporary (historical) control animals. These included anal atresia, cleft palate, vestigal tail, and vertebral agenesis. The NOAEL for both maternal and developmental toxicity in the rat was 1800 ppm. Pregnant and virgin female Swiss (CD-1) mice were exposed to 0, 600, 1800 or 5000 ppm of tetrahydrofuran vapors whole-body for 6 hours/day, 7 days/week on DG 6 to 17. Due to an unexpectedly high rate of toxicity at the highest exposure concentration, exposures were discontinued on DG 11 (total of 6 exposures). A total of 30% of exposed virgin female mice died during exposure days 1 through 5. Severe central nervous system depression was proposed as causing or contributing to death. Sedation lasting for up to 1 hour following exposures was observed in all animals in the 5000 ppm exposure group as well as some animals in the 1800 ppm exposure group. Exposures to THF had no effect on the number of implantations/dam. The number and percentage of live fetuses/litter in both the 1800 and 5000 ppm exposure groups were reduced compared to controls. Neither fetal weights nor fetal sex ratios were affected by exposures at 1800 or 5000 ppm. Because only a single litter with live fetuses was present at the 5000 ppm exposure concentration, statistical analysis at this level was not possible. Although not statistically significant, several malformations were observed at low incidences in the 1800 ppm group that were not present either in the 0 ppm controls or contemporary controls: cleft palate, edema, ectopic ovaries, and undescended testes. These latter malformations were all observed in fetuses from a single low-weight litter that also had a 54% incidence of resorptions. There was an increased incidence of reduced ossifications of the sternebrae in the 1800 ppm exposure group and these correlated with increasing exposure concentrations. Tetrahydrofuran, although showing clear evidence of embryotoxicity in Swiss CD-1 mice, was not judged to be a selective developmental toxicant in the CD-1 mouse. This appraisal is based on the clear presence of maternal toxicity at the highest dose level and extending to the 1800 ppm dose level. The NOAEL for maternal toxicity in the current study was 600 ppm. The NOAEL for developmental toxicity was 600 ppm. In a second study in rats, THF was administered to pregnant rats by whole-body inhalation from Days 6 through 15 of gestation at nominal concentrations of 0, 200, 500, 2500 and 5000 ppm (Part 1) or 0, 1000 and 5000 ppm (Part 2). There was no maternal mortality but the highest exposure concentration (5000 ppm) was toxic to the dams; toxic responses included significant decreases in feed consumption and body weight gain during the exposure period, lethargy and incoordination, and an absence of response to a noise stimulus. A reduced response to a noise stimulus was also observed at the 1000 and 2500 ppm exposure concentrations. Malformations were not increased following exposure to THF but fetuses at the highest exposure concentration had reduced body weights and sternebral ossification was less that control. Embryotoxicity, expressed as developmental delay, occurred only at 5000 ppm and in the presence of maternal toxicity. Thus, THF was not selectively toxic to the developing rat conceptus in this study.

Toxicity to reproduction: other studies

Additional information

Male and female F344/N rats and male and 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. Full histopathological analysis was performed on reproductive organs including the preputial gland (rats), prostate, testis and uterus. In rats, there were no reported pathological effects. Female mice displayed uterine atrophy at the highest exposure concentration, manifested as small uteri and microscopically by fewer numbers of uterine glands. The uterine atrophy observed in this study may represent an acceleration of a normal aging process. Male and female F344 rats and male and 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. Full histopathological analysis was performed on reproductive organs including the preputial gland, prostate, testis and uterus. There were no significant histopathological effects reported in rats. In mice, 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

Tetrahydrofuran is not a selective developmental toxicant based on studies conducted in Wistar rats and in Swiss CD-1 mice. In mice, embryotoxicity was observed at an inhalation exposure concentration (1800 ppm) also causing significant maternal effects. Similaryly in rats, no selective effect on the developing fetus is observed. Based on the evidence presented, tetrahydrofuran should not be rated as a reproductive hazard (Substances which cause concern for human fertility) under the EU DSD classification system (EU Directive 647/548/EEC). Similarly, tetrahydrofuran would not be rated under the EU CLP classification system (EU Regulation 1272/2008).