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Repeated dose toxicity: inhalation

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sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10 February 1987 to 14 May 1987
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Studies were conducted according to generally valid and/or internationally accepted testing guidelines.

Data source

Referenceopen allclose all

Reference Type:
Reference Type:
study report
Report Date:

Materials and methods

Test guideline
according to
other: According to the specification of the National Toxicology Program for the conduct of toxicity and carcinogenicity studies on chemicals
GLP compliance:
Limit test:

Test material

Details on test material:
- Name of test material: tetrahydrofuran- Supplier: ChemCentral, Kansas City, MO, USA- Physical state: clear, colorless liquid- Analytical purity: approximately 99% (determined by gas chromatography)- Impurities: none identified greater than 0.1%- Purity test date: not provided- Lot/batch No.: lot WK8-6-86- Expiration date of the lot/batch: not provided- Stability under test conditions: stability studies indicated that tetrahydrofuran was stable as the bulk chemical for 2 weeks when stored protected from light at temperatures up to 25 deg C. Stability was monitored during the 14-week studies and no degradation of the bulk chemical was detected.- Storage condition of test material: at room temperature in the original metal containers under a nitrogen blanket- Other: Karl Fischer analysis indicated less than 0.06% water; peroxide concentrations were less than 1.5 ppm

Test animals

Fischer 344
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Simonsen Laboratories, Inc., Gilroy, CA- Age at study initiation: 7 weeks (average)- Weight at study initiation: not available- Fasting period before study: No- Housing: Stainless-steel wire-bottom (Hazleton Systems, Inc., Aberdeen, MD), 1 animal/cage.- Diet: NIH-07 Open Formula Pelleted feed, ad libitum except during exposures- Water: Tap water (City of Richland municipal supply), ad libitum- Acclimation period: quarantined 13 days before the beginning of the studiesENVIRONMENTAL CONDITIONS (Exposure Chambers)- Temperature: 19.6 to 26.6 °C- Humidity (%): 29 to 75- Air changes (per hr): 15 +/- 3- Photoperiod (hrs dark / hrs light): 12/12IN-LIFE DATES: From: 10 February 1987 To: 13 May 1987

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
other: conditioned air
Details on inhalation exposure:
Vapor Generation/Exposure System:Tetrahydrofuran vapor was generated with a rotary evaporation system (Buchi Rotavapor, Model EL-131S, Buchi Laboratories Technik AG, Flavil, Switzerland). The vapor entered a short distribution manifold from which individual delivery lines carried metered amounts of the vapor to each exposure chamber. At equilibrium, each valve was opened to allow flow to chambers. At each chamber location, the vapor was injected into the chamber duct after dilution with an appropriate amount of charcoal- and HEPA-filtered chamber air to achieve the desired chamber concentration.The exposure system consisted of stainless-steel chambers designed at Batelle Northwest Laboratories (Hazelton 2000, Aberdeen, MD).
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
Vapor Concentration Monitoring:Exposure concentrations were monitored by an on-line gas chromatograph. Samples were drawn from each exposure chamber, the control chamber, the exposure suite, the on-line standard, and a filtered air blank (see Table 1).Chamber Atmosphere Characterization:The times for the exposure concentrations to build up to 90% of the final exposure concentration (T90) and to decay to 10% of the exposure concentration (T10) were measured in all studies with and without animals in the chambers. The T90 value chosen for all studies was 12 minutes. Actual T90 values ranged from 5 to 15 minutes with or without animals. T10 values ranged from 7 to 10 minutes without animals and 9 to 14 minutes with animals. Uniformity of exposure concentrations in all chambers was acceptable.All lots of tetrahydrofuran contained 2,6-di-tert-butyl-4-methylphenol (BHT) as a stabilizer. BHT is less volatile than tetrahydrofuran and was expected to be depleted in the generated chamber atmospheres. BHT and peroxide concentrations were determined from samples taken from the generator reservoir for tetrahydrofuran stability analyses. No contaminants or degradation was products were found during the 14-week studies. Results indicated that tetrahydrofuran was stable in the generator reservoir.
Duration of treatment / exposure:
14 weeks
Frequency of treatment:
6 hours plus T90 (12 minutes) per day, 5 days/week
Doses / concentrations
Doses / Concentrations:0 (chamber control), 66, 200, 600, 1800 and 5000 ppmBasis:nominal conc.
No. of animals per sex per dose:
Control animals:
yes, concurrent no treatment
Details on study design:
The 14-week studies in rats were conducted to evaluate the cumulative toxic effects of repeated exposure to tetrahydrofuran and to determine the appropriate exposure concentrations to be used in the 2-year studies.


Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS:- Time schedule: all animals were observed twice daily.DETAILED CLINICAL OBSERVATIONS:- Time schedule: clinical findings were recorded weekly.BODY WEIGHT:- Time schedule for examinations: animals were weighed initially, weekly, and at the end of the studies.HAEMATOLOGY:- Time schedule for collection of blood: at the end of the 14-week exposures- Anaesthetic used for blood collection: No data- Animals fasted: No- How many animals: all study animals- Treatment of blood: placed in collection tubes containing potassium EDTA- Parameters measured: erythrocyte and leukocyte counts, hematocrit, hemoglobin concentration, mean cell volume, mean cell hemoglobin concentration, and platelet counts were all measured on a Ortho ELT-8/ds hematology counter (Ortho Instruments, Westwood, MA). Differential leukocyte counts, blood cell morphology, and nucleated erythrocyte counts were determined by light microscopic examination of blood films stained with Wright-Giemsa. Reticulocytes were counted as reticulocyte/erythrocyte ratio using a Miller disc.CLINICAL CHEMISTRY:- Time schedule for collection of blood: at the end of the 14-week exposures- Animals fasted: No- How many animals: all study animals- Treatment of blood: collected in tubes without coagulant and allowed to clot- Parameters measured: urea nitrogen, creatinine, total protein, albumin, alanine aminotransferase, alkaline phosphatase, creatine kinase, sorbitol dehydrogenase, and bile acids.
Sacrifice and pathology:
Necropsy:Animals were sacrificed by carbon dioxide asphyxiation and complete necropsies were performed on all study animals. Organs weighed included heart, liver, lung, right kidney, spleen, and thymus.Histopathology:Complete histopathology was performed on all chamber control and 5000 ppm rats and all others with gross lesions, and target organs in lower exposure groups to a no-effect level.In addition to gross lesions and tissue masses, the following tissues were examined: adrenal gland, brain, clitoral gland (rats), esophagus, heart with aorta, large intestine (cecum, colon, rectum), small intestine (duodenum, jejunum, ileum), kidney, larynx, liver, lung and mainstem bronchi, lymph nodes (mandibular, mesenteric, bronchial, & mediastinal), mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland (rats), prostate gland, salivary gland, skin, spleen, sternebrae (with marrow), stomach (forestomach and glandular), testis, thymus, thyroid gland, trachea, urinary bladder, and uterus.
Resutls were reported as mean with standard deviation. Differences from chamber controls for organ weights or organ-to-body weights were analyzed with William's or Dunnett's test. Differences from chamber controls for hematology or clinical chemistry were analyzed with Dunn's or Shirley's test.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITYAll animals survived until study termination. Immediately after exposures, male and female rats in the 5000 ppm exposure group exhibited ataxia, which was described as irregular movement with lack of coordination.BODY WEIGHT AND WEIGHT GAINFinal mean body weights and body weight gains of exposed male and female rats were similar to those of the chamber controls. Final mean body weights as a percentage of chamber controls were as follows:Males: 98% (66 ppm), 102% (200 ppm), 101 (600 ppm), 102 (1800 ppm), and 96 (5000 ppm)Females: 100% (66 ppm), 99% (200 ppm), 103 (600 ppm), 101 (1800 ppm), and 103 (5000 ppm)HAEMATOLOGYHematologic differences were generally minimal, with most values falling within physiologic ranges. The differences noted did not demonstrate a strong exposure relationship and statistically significant differences only occurred in the 5000 ppm groups; although this may represent a biologic effect. The values for selected hematological parameters for the chamber control and dosed groups were as follows:Hematocrit (%, male): 46.1, 45.9, 46.2, 46.0, 46.5, 49.2 (p

Effect levels

Dose descriptor:
Effect level:
1 800 ppm
Basis for effect level:
other: Changes in hematological and clinical chemistry (most values minimal and falling within normal physiologic ranges); acanthosis and inflammation of the forestomach at the highest exposure concentration (5000 ppm).

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

Groups of 10 male and 10 female F344/N rats were exposed to 0 (chamber control), 66, 200, 600, 1800 or 5000 ppm tetrahydrofuran by inhalation, 6 hours/day, 5 days/week, for 14 weeks. All male and female F344/N rats exposed to tetrahydrofuran for 6 hours/day, 5 days/week, for 14 weeks at exposure concentrations as high as 5000 ppm survived. Immediately after exposures, male and female 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.