Tetrahydrofuran

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1988

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Conducted according to generally recoginized international guidelines. Equivalent to an OECD 407 Guideline study. However, the highest dose level of 1000 mg/l in drinking water gave only an approximate dose of 111.3 mg/kg bwt/day.

Data source

Reference

Reference Type:

publication

Title:

Results of a Short-Term Toxicity Study for Three Organic Chemicals Found in Niagara River Drinking Water

Author:

Komsta, E., Chu, I., Secours, V.E., Valli, V.E., and Villeneuve, D.C.

Year:

1988

Bibliographic source:

Bulletin of Environmental Contamination and Toxicology Vol. 41:515-522 (1988)

Materials and methods

Principles of method if other than guideline:

The protocol followed was generally equivalent to that of OECD Guideline 407. Tetrahydrofuran was administered in the drinking water of rats at concentrationls up to 1000 mg/l. Animals were observed for toxicological effects. Pathologic and hematologic analyses were performed following sacrifice.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Tetrahydrofuran

EC Number:

203-726-8

EC Name:

Tetrahydrofuran

Cas Number:

109-99-9

Molecular formula:

C4H8O

IUPAC Name:

tetrahydrofuran

Details on test material:

- Name of test material (as cited in study report): Tetrahydrofuran- Analytical purity: 99.5%- Supplier: BDH Chemicals (Toronto, Ontario)- Other: The purity and identity were confirmed by thin-layer chromatographic, gas chromatographic, and gas chromatographic-mass spectrometric techniques.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Source: Charles River Laboratories- Age at study initiation: young adult- Weight at study initiation: males, 215-217 g; females, 116-122- Fasting period before study: no- Housing: individually, stainless-steel wire mesh cages- Diet (ad libitum): source not stated- Water (ad libitum): presumably tap water- Acclimation period: 1 week prior to treatmentsENVIRONMENTAL CONDITIONS- Temperature (°C): 21 +/- 2- Humidity (%): 40-60- Air changes (per hr): not stated- Photoperiod (hrs dark / hrs light): not stated

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:Solutions were prepared by dissolving the appropriate amounts of test article directly in tap water.APROXIMATE AMOUNT OF TEST CHEMICAL INGESTED:The approximate amounts of tetrahyrofuran ingested at the 1, 10, 100 and 1000 mg/l concentrations in drinking water were as follows:males (g/kg bwt/day): 0.1, 0.8, 10.5, 95.5.females (g/kg bwt/day): 0.1, 0.1, 10.7, 111.3

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

4 weeks

Frequency of treatment:

continuous

Doses / concentrations

Remarks:

Doses / Concentrations:0, 1.0, 10, 100 or 1000 mg/lBasis:nominal in water

No. of animals per sex per dose:

10

Control animals:

yes

Details on study design:

Test animals were randomly divided into groups of 10/sex/dose level and were given tetrahydrofuran in their drinking water for 4 weeks. Control animals received tap water.

Positive control:

None stated

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes- Time schedule: Clinical observations performed daily.BODY WEIGHT: Yes- Time schedule for examinations: Body weight gain were measured weekly.FOOD CONSUMPTION: - Time schedule for examinations: Food consumption was measured weekly.WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes- Time schedule for examinations: Water consumption was measured weekly and approximate test material ingested was determined.HAEMATOLOGY: Yes- Time schedule for collection of blood: at study termination- Anaesthetic used for blood collection: light ether anesthetic, exsanguination via the abdominal aorta- Animals fasted: No- How many animals: animals- Parameters examined: hemoglobin, packed-cell volume, erythrocyte count (Baker 7000), total and differential leukocyte counts and platelet count.CLINICAL CHEMISTRY: Yes- Time schedule for collection of blood: at study termination- Animals fasted: No- How many animals: all- Parameters examined: Serum biochemical measurements were performed on a Technicon microanalyzer (Model 12/60 micro) and included sodium, potassium, inorganic phosphate, total bilirubin, alkaline phosphatase (AP), aspartate aminotransferase (AST), total protein, calcium, cholesterol, glucose, uric acid and lactic acid (LDH). Hepatic microsomal aniline hydooxylase (AH; Fouts, 1963), aminopyridine demethylase (ER; Burke and Mayer, 1974) acitivities were determined using published methods.URINALYSIS: NoNEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: YesAt the time of sacrifice, all animals were examined grossly.TISSUE COLLECTION/ORGAN WEIGHTS:At necropsy, the brain, heart, liver, spleen and kidneys were removed and weighed.HISTOPATHOLOGY: YesSelected tissues from the control and high dose groups were fixed in 10% neurtral buffered saline for routine histological examinations. The tissues examined histologically included: brain, pituitary, liver, adrenal, thyroid, parathyroid, thymus, lungs, trachae, bronchi, thoracid, aorta, esophagus, gastric cardia, fundus and pylorus, duodenum, pancreas, colon, kidney, testes and epidiymis in the male, ovaries and uterus in the female, and skeletal muscle and heart. Potential fatty changes in the liver were determined in frozen sections as per Villeneuve et al. (1979).

Statistics:

Data were analyzed by one-way analysis of variance. If significant differences were observed among groups (p<0.05), data were analyzed with Duncan's multiple range test.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

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:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITYThere were no clinical signs of toxicity. All animals survived until study termination.BODY WEIGHT AND WEIGHT GAINWeight gains for all treated groups were not statistically different from those of the controls.FOOD CONSUMPTIONFood consumption for all treated groups was not statistically different from that of the controls.WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)Water consumption for all treated groups was not statistically different from that of the controls.HAEMATOLOGYThere were no significant hematological effects reported in this study.CLINICAL CHEMISTRYThere were no biochemical changes noted for tetrahydrofuran.ORGAN WEIGHTSNo significant organ weight changes were noted in this study.GROSS PATHOLOGYA dilated renal pelvis was observed in one male rat at the 100 mg/l concentration.HISTOPATHOLOGY: NON-NEOPLASTICEffects generally mild in nature were observed in the thyroid, liver, and kidneys (see Table 1).

Effect levels

Dose descriptor:

NOAEL

Effect level:

1 000 mg/L drinking water

Sex:

male/female

Basis for effect level:

other: Minimal to mild changes in the liver, kidneys and thyroid were not accompanied by biochemical or hematological changes and were considered to be adaptive in nature.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table 1: Prevalence of Histological Changes in Rats Administered Tetrahydrofuran at 1000 mg/l in Drinking Water

Tissues	Control (males)	Prevalence (males)*	Conrtol (females)	Prevalence (females)
Thyroid
- Reduced follicular size	5/0	3/0	2/0	3/0
- Increased epithelial height	1/0	1/0	0/0	0/0
- Reduced colloid density	0/0	2/0	0/0	1/0
Liver
- Anisokaryosis	0/0	3/0	0/0	7/1
- Increased cytoplasmic homogeneity	3/0	7/0	1/0	0/0
Kidney
- Glomerular adhesions	6/0	6/1	8/0	7/0
- Tubular cytoplasmic inclusions	2/0	1/0	0/0	3/0

* Values denote: number of animals with minimal/mild changes / number of animals with moderate to severe changes.

Applicant's summary and conclusion

Conclusions:

Tetrahydrofuran, administered in drinking water, produced no clinical signs of toxicity nor changes in weight gain or food or water consumption at doses of up to 111.3 mg/kg bwt/day (females). There were no significant biochemical or hematological changes noted. Histopathologically only minimal to mild 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.