Tetrahydrofuran

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

4 September 1978 to 20 November 1978

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to an accepted and published method. However, the study was conducted prior to modern protocol and GLP requirements.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1978

Report date:

1978

Materials and methods

Principles of method if other than guideline:

Conducted according to a published procedure (Hagan, E.C. (1959). Acute Toxicity: Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics, pp. 17-25.

GLP compliance:

no

Test type:

standard acute method

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- Lot/batch No.: Sample No. 7427-F- Other: Received from GAF Corporation on August 25, 1978

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Source: Summit View Farm, Belvedere, New Jersey (USA)- Weights at study initiation (definitive study): 180 - 240 g (females); 200 - 256 g (males)- Fasting period before study: fasted overnight prior to test chemical administration- Housing: maintained under standard laboratory conditions- Diet (ad libitum): Wayne animal feeds- Water (ad libitum): source not stated- Acclimation period: 7 days prior to test chemical administration

Administration / exposure

Route of administration:

oral: gavage

Details on oral exposure:

Material used as received (Specific Gravity: 0.90). A 40 mL/kg bwt top dose was indicated as the maximum feasible.

Doses:

Range finding study: 0.5, 1.0, 3.0, and 5.0 g/kg bwtDefinitive study: 0.50, 1.26, 2.00, 2.00, 2.52 and 4.00 g/kg bwt

No. of animals per sex per dose:

A single animal was used at each dose level in the range-finding study. Six animals (3 male, 3 female) were used at each dose level in the definitive study.

Control animals:

no

Details on study design:

- Duration of observation period following administration: animals were observed at 1, 3, 6 and 24 hours and daily thereafter for a total of 14 days.- Frequency of observations and weighing: Presumed once daily- Necropsy of survivors performed: complete gross necropsy performed on animals sacrificed at the end of the 14-day observation period.- Other examinations performed: animals were observed for signs of pharmacological activity and drug toxicity

Statistics:

The LD50 value in the definitive study was calculate by the method of Litchfield and Wilcoxin (1949, J. Pharmacol. Exptl. Therap., pp. 96-99).

Results and discussion

Preliminary study:

In a preliminary range finding study, a single animal (male or female) was dosed at 0.5, 1.0, 3.0 or 5.0 g/kg bwt and observed for signs of toxicity at 1, 3, 6 and 24 hours and daily up to 14 days. The animal (male) dosed at 0.5 g/kg bwt survived and appeared normal. The animal (male) dosed at 1.0 g/kg bwt died between days 7 to 14 (not specified). This latter animal appeared normal, with no gross changes. The single animal (female) dosed at 3.0 g/kg bwt displayed severe depression up to hour 6 of observation and was dead by 24 hours. No gross changes were observed in this animal. The single animal (female) dosed at 5.0 g/kg bwt died within 1 hour following dosing. The gastro-intestinal tract mucosa was severely reddened in this animal.

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1.65 mg/kg bw

95% CL:

1.25 - 2.19

Mortality:

In the definitive study, the following rates of mortality of male and female rats were reported:- Test dosage 0.50 g/kg bwt: 1/3 males and 2/3 females (50%)- Test dosage 1.26 g/kg bwt: 2/3 males and 0/3 females (33%)- Test dosage 2.00 g/kg bwt: 1/3 males and 2/3 females (50%)- Test dosage 2.00 g/kg bwt: 2/3 males and 3/3 females (83%)- Test dosage 2.52 g/kg bwt: 2/3 males and 2/3 females (67%)- Test dosage 4.00 g/kg bwt: 3/3 males and 3/3 females (100%)

Clinical signs:

other: Please refer to the remarks section.

Gross pathology:

Please refer to the remarks section.

Any other information on results incl. tables

At the 0.50 g/kg bwt dosage, a single male rat died on day 14 and displayed fibrous tissue encasing the heart and lungs. Two female rats died at the 0.50 g/kg bwt dosage: a single female dying on day 13 displayed pyloric and intestinal mucosa reddening; a second female rat dying on day 12 displayed no gross changes. One death at this dose level was not considered dose related and was not used for the purpose of calculating an LD50 value.

At the 1.26 g/kg bwt dosage, two male rats died prior to scheduled necropsy. A single male rat was observed to be depressed (hours 1 and 6) or severely depressed (hour 3) but then appeared normal at 24 hours and until death on day 9. This animal displayed no gross changes. A second male rat at this dosage displayed depression (hours 1, 3 and 6) and slight depression (24 hours and day 2) with death on day 3. This animal displayed no gross changes. The single surviving male rat at this dosage displayed depression (hours 1, 3, 6) and slight depression (24 hours) but then appeared normal until study termination. This surviving male rat displayed a partially consolidated left lung. All female rats displayed depression or slight depression up to hour 6 but then, with the exception of one animal, appeared normal until study termination. Slight depression was observed on day 14 for a single female rat. Female rats displayed no gross changes.

Two groups of six animals (3 male/3 female) were dosed at the 2.00 g/kg bwt dose level. In the first, a single male rat died on day 13 and appeared normal up to death. Two female rats died: the first displayed depression on day 2 and died on day 3, this animal had fibrous tissue encasing the heart and lungs; a second female rat appeared normal but died on day 11, this animal displayed no gross changes. In a second group of animals dosed at 2.00 g/kg bwt, a considerably different response was reported. All but a single male rat survived until study termination. A single male rat displayed severe depression (hours 1, 3 and 6) or depression (24 hours and days 2 and 3) with death on day 3. This animal displayed no gross changes. A second male rat displayed severe depression (hours 1 and 6), slight depression (24 hours), or depression (hour 3 and days 2 and 3) but appeared normal on the day of death (day 4). The single surviving male rat displayed severe depression (hours 1, 3, and 6), slight depression (24 hours and day 3), or depression (day 2), but then appeared normal until sacrifice. All female rats died in the second group of 2.00 g/kg animals. A single female rat displayed severe depression (hours 1, 3, and 6) and slight depression (24 hours) and died on day 2. The pyloric mucosa of this female rat was moderately reddened. A second female rat displayed severe depression (hours 1, 3 and 6), depression (day 2) or slight depression (24 hours or day 3) but appeared normal on day 4 with death on day 5. This animal displayed no gross changes. A third female rat displayed severe depression (hours 1, 3, and 6), depression (24 hours), and slight depression (24 hours and days 3 and 6) but appeared normal prior to death on day 10. This animal displayed no gross changes.

At the 2.52 g/kg bwt dosage level, only 2 of 6 animals (1 male and 1 female) survived until scheduled sacrifice. The single surviving male displayed severe depression (hours 1, 3 and 6) or slight depression (24 hours and day 2) but then appeared normal for the duration of the study. In this surviving animal, the cardiac portion of the stomach and left lobe of 1.0 cm adhered to the body wall, diaphragm, and each other. A second male rat displayed severe depression (hour 1) and died by 3 hours. This animal displayed reddened pyloric and intestinal mucosa. A third male rat displayed severe depression (hours 1, 3 and 6) or slight depression (24 hours and day 2) but then appeared normal until death on day 10. No gross changes were observed in this animal. The single surviving female rat displayed severe depression (hours 1, 3 and 6) but then appeared normal until day 14 (sacrifice) at which time slight depression was noted. In this surviving female rat, the entire left lung was consolidated; also, the cardiac portion of the stomach wall was thickened and adhered to the body wall and diaphragm. The remaining two female animals displayed severe depression (hours 1, 3 and 6) with death by 24 hours. However, there were no gross changes observed in these latter animals.

At the 4.00 g/kg bwt dosage level, all rats died before the scheduled termination. A single male rat displayed severe depression (hour 1) and died by hour 3. This animal had test material in the stomach and the pyloric mucosa was severely reddened. Both remaining male rats died by hour 1, however, no gross changes were observed in these animals. Two female rats displayed severe depression (hour 1) and died by hour 3. One of these rats displayed moderately reddened pyloric and intestinal mucosa, however, the second displayed no gross changes. A third female rat displayed severe depression (hour 1), depression (hours 3 and 6) but then appeared normal until death on day 3. This latter animal displayed no gross changes.

Applicant's summary and conclusion

Interpretation of results:

other: Xn;R22 (Harmful if swallowed)

Remarks:

Criteria used for interpretation of results: other: under the EU DSD classification criteria (EU Directive 67/548/EEC)

Conclusions:

The LD50 of tetrahydrofuran in male and female Wistar-derived rats following oral gavage was 1.65 g/kg.

Executive summary:

Groups of 6 male and female Wistar-derived rats were dosed by gavage with tetrahydrofuran at dose levels of 0.5, 1.26, 2.00, 2.00, 2.52 or 4.00 g/kg bwt and observed for signs of pharmacologic activity or drug toxicity at 1, 3, 6 and 24 hours and daily thereafter up to 14 days. Animals sacrificed at the end of the 14-day observation period were subjected to complete necropsy. Signs observed prior to death were reported as depression, ranging from slight to severe. Although not consistently observed in either surviving rats or rats dying prior to scheduled necropsy, several gross pathological findings were reported including: fibrous tissue encasing the heart and lungs; reddening of pyloric and intestinal mucosa; lung consolidation; the cardiac portion of the stomach thickened and adhered to body wall and diaphragm; and the presence of test material in the stomach (4.00 g/kg bwt dose level). No cause of death was reported in this study. The calculated LD50 (male and female combined) was 1.65 g/kg bwt.