Tetrahydrothiophene

Endpoint summary

Description of key information

The acute oral median lethal dosage (LD50) in rats was 1,850 mg/kg. Signs of reaction to treatment included tremors, ataxia, respiratory abnormalities, inappetence and body weight loss. Recovery was complete within a few days. The dermal LD0 in rabbits was in excess of 2,000 mg/kg. The acute inhalation median lethal concentration (LC50) in rats (4-hour exposure) was 6,270 ppm (22572 mg/m3). Signs included secretory increases, respiratory abnormalities and body weight losses.

 

Oral route

In an acute oral toxicity study performed according to EPA guideline #OTS 798.1175 and GLP (Auletta, 1985), Tetrahydrothiophene was administered to male and female Sprague-Dawley rats at dose levels of 800, 1000, 1250, 1600, 2000, 3125 mg/kg. Most surviving males exhibited weight gains at Day 7, although several females in the 1000, 1250 and 1600 mg/kg groups showed slight weight losses. All surviving gained weight between Days 7 and 14; gains were generally comparable among groups. Pharmacological and toxicological signs seen in all groups during the 24 hours after dosing included ataxia, tremors, hypoactivity and/or prostration, oral discharge, various respiratory abnormalities. Postmortem examinations of animals which were found dead revealed a variety of changes, primarily in the lungs and gastrointestinal tract. The LD50’s were 2000 (1387-2613) mg/kg, 1750 (1268-2232) mg/kg and 1850 (1547-2153) mg/kg for male, female and combined sex rats, respectively.

 

Inhalation

A series of groups consisting of five male and five female Sprague-Dawley rats was whole-body exposed to tetrahydrothiophene vapors for four hours at mean analytical levels in the range of 3090 to 6300 ppm (11142 to 22718 mg/m3). The study was performed according to EPA guideline #OPP 81-3 and GLP (Terrill, 1986). Signs attributable to treatment included death, increased incidences of secretory responses, respiratory distress, reduced activity, matted coat, prostration, poor condition, ano-genital area staining and loss of body weight. Overall, the time-to-onset and time-to-recovery of these signs appeared to be related to exposure concentration. The resultant median lethal concentration values were 6270 ppm (22572 mg/m3) for the combined sexes.

 

Sprague-Dawley derived rats (5/sex/group) were exposed by inhalation for six hours at analytical concentrations of 0 or 1011 ppm (3640 mg/m3) vapour of tetrahydrothiophene (Daly, 1986) and were observed for 7 days. Detailed physical examinations were conducted daily, post-exposure, on all animals. Body weight measurements were recorded pretest, the first, third and fifth days, and before necropsy. On Test Day 8, all survivors were sacrificed and complete gross postmortem examinations and histopathological evaluations of selected tissues were conducted on all animals. No treatment-related deaths occurred during the study. Increased secretory responses, respiratory distress and reduced activity were observed during both exposure and non-exposure periods. The relationship between incidence and exposure concentration was not sharply defined and it was concluded the findings might be more of a physiological response to the test substance, which is a mal-odorant, than a toxicological response. In the lungs, interstitial inflammation and concomitant alveolar emphysema, while of comparable incidence in the treated and control animals, tended to be somewhat more severe in the treated animals. Collapsed and/or atelectatic alveoli were observed somewhat more frequently in the lungs of the treated animals than in their comparable controls; the toxicological significance of this finding, if any, remains equivocal. Results for body weight determinations were considered unremarkable. From the clinical signs observed during exposure a LOAEC of1011 ppm (3640 mg/m3) can be established for the local irritation of the respiratory tract.

 

Dermal

In an acute dermal toxicity study performed according to EPA guideline #OTS 798.1100 and GLP (Auletta, 1985), tetrahydrothiophene was administered to male and female New-Zealand rabbits at the dose level of 2000 mg/kg. All animals survived throughout the study. Most animals exhibited severe dermal effects at the dose site (necrosis followed by eschar formation, fissuring and/or exfoliation of the eschar tissue) which persisted throughout the study. Most animals exhibited hyperpnea on the day of dosing. Other signs seen in one or two animals on the day of dosing included fine tremors, nasal discharge, dyspnea, arythmic respiration and red eyes. Gross postmortem observations confirmed the presence of dermal lesions discussed previously. Unusual observations included surface irregularities (wrinkling) of the spleen in five animals, discoloured kidneys (mottled tan) in three animals and fissures in the liver in two animals. The dermal LD0 of tetrahydrothiophene in rabbits is greater than 2000 mg/kg body weight.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Qualifier:

according to guideline

Guideline:

EPA OTS 798.1175 (Acute Oral Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding laboratoryies Inc. (Wilmington, MA, USA)
- Age at study initiation: 9-12-week old
- Weight at study initiation: 268-360 g (males); 220-256 g (females)
- Fasting period before study: 18 h
- Housing: individually in suspended, stainless steel cages
- Diet (e.g. ad libitum): Purina Loaboratory Chow, 5001
- Water (e.g. ad libitum): municipal water
- Acclimation period: 15 or 21 days

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 67-76
- Humidity (%): 30-70
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

800, 1000, 1250, 1600, 2000, 3125 mg/kg

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

EXPERIMENTAL EVALUATION
The following observations were made on animals which were dosed for LD50 determination.
Viability Check: Twice Daily
Clinical signs of toxicity: Approximately 1, 2, and 4 hours after dosing and daily thereafter for fourteen days.
Body Weights: Pre-fast (weights used for calculation of doses), Day 7 and Day 14.
Terminal: Any animals which did not survive for 14 days were weighed at the time of death or at the time they were found dead.

POSTMORTEM
Gross postmortem examinations were performed on all animals which died or were found dead during the study. All animals surviving at termination of the observation period (Day 14) were killed by carbon dioxide inhalation and examined grossly. All abnormalities were recorded but no tissues were saved.

Statistics:

LD50 was calculated using the following method: Miller, Lloyd C. and M.L. Tainter., Estimation of the ED50 and Its Error by Means of Logarithmic-Probit Graph Paper, Proc. Soc. Exp. Bio. Med. 57: 261-264 (1944).

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 850 mg/kg bw

95% CL:

1 547 - 2 153

Mortality:

Dose levels, mortality and the estimated LD50 with 95% confidence limits were as follows:
Mortality
Dose Level male female total Time of Death
mg/kg
800 0/5 1/5 1/10 24 Hr
1000 0/5 0/5 0/10 -
1250 1/5 0/5 1/10 24 Hr
1600 0/5 3/5 3/10 24 Hr-Day 2
2000 2/5 4/5 6/10 24 Hr-28 Hr
3125 6/6 4/4 10/10 24 Hr-28 Hr

LD50 (mg/kg): 2000 1750 1850
95% Confidence
Limits (mg/kg): 1387- 1268- 1547-
2613 2232 2153

Clinical signs:

Signs seen in all groups during the 24 hours after dosing included ataxia, tremors, hypoactivity and/or prostration, oral discharge, various respiratory abnormalities and decreased food consumption. Two animals, one in the 1000 mg/kg group and one in the 2000 mg/kg group, had discolored (red or dark brown) urine. Other observations occurred sporadically. Although some abnormalities were still apparent on Days 2 and 3, most survivors were free of unusual signs from Day 4 through study termination (Day 14).

Body weight:

Most surviving males exhibited weight gains at Day 7, although several females in the 1000, 1250 and 1600 mg/kg groups showed slight weight losses. All surviving gained weight between Days 7 and 14; gains were generally comparable among groups.

Gross pathology:

Postmortem examinations of animals which were found dead revealed a variety of changes, primarily in the lungs and gastroinestinal tract. A few animals had red or black material in the stomach and intestine and red or black discoloration of the gastrointestinal mucosa. Several had apparent test material in the gastrointestinal tract. One animal in the 1250 mg/kg group had red fluid in the urinary bladder. Other changes in animals found dead appeared to represent autolytic changes. Changes in animals killed after 14 days were similar to those seen in control animals killed by carbon dioxide inhalation in the laboratory.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The LD50's were 2000 (1387-2613) mg/kg, 1750 (1268-2232) mg/kg and 1850 (1547-2153) mg/kg for male, female and combined sex rats, respectively.

Executive summary:

In an acute oral toxicity study performed according to EPA guideline #OTS 798.1175 and GLP, tetrahydrothiophene was administered to male and female Sprague-Dawley rats at dose levels of 800, 1000, 1250, 1600, 2000, 3125 mg/kg.

Most surviving males exhibited weight gains at Day 7, although several females in the 1000, 1250 and 1600 mg/kg groups showed slight weight losses. All surviving gained weight between Days 7 and 14; gains were generally comparable among groups. Clinical signs of toxicity seen in all groups during the 24 hours after dosing included ataxia, tremors, hypoactivity and/or prostration, oral discharge, various respiratory abnormalities. Postmortem examinations of animals which were found dead revealed a variety of changes, primarily in the lungs and gastroinestinal tract.

The LD50's were 2000 (1387-2613) mg/kg, 1750 (1268-2232) mg/kg and 1850 (1547-2153) mg/kg for male, female and combined sex rats, respectively.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 850 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Qualifier:

according to guideline

Guideline:

EPA OPP 81-3 (Acute inhalation toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Wilmington, MA
- Age at study initiation:
Males: 7-8 weeks
Females: 9-10 weeks
- Weight at study initiation:
Males: 209-291 g
Females: 202-220 g
- Fasting period before study:
- Housing: individually housed in stainless steel wire cages
- Diet (e.g. ad libitum): Purina Rodent Laboratory Chow #5001
- Water (e.g. ad libitum): tap water
- Acclimation period: 1 to 3 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 67-76
- Humidity (%): 30-70
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: To:

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

The Plexiglas exposure chamber had a total volume of 100 liters. The chamber was operated dynamically at a calibrated air flow rate of 25 liters per minute (lpm). This flow rate was calculated to provide one complete air change every 4 minutes and a 99% equilibrium time of 18.4 minutes. Approximately 300 milliliters (mls) of the test substance was placed in each of two 500 ml bubblers fitted with impingers. House-supply air was delivered via a Dwyer flowmeter and a Nupro metering valve to the two bubblers and into a 3-neck flask. Additional diluted air was delivered to the 3-neck flask via a Nupro metering valve and a Dwyer flowmeter. The resultant vapor-laden air stream was directed from the 3-neck flask into the 100 liter Plexiglas exposure chamber.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

Samples for determination of tetrahydrothiophene vapor exposure levels were taken using a MIRAN lA Ambient Air Analyzer and strip chart recorder (Fisher Recordall Series 5000). The exposure level of tetrahydrothiophene was determined by the resultant

Duration of exposure:

4 h

Concentrations:

0, 3090, 4400, 5260, 5670 and 6300 ppm (11142, 15866, 18968, 20446 and 22718 mg/m3, analytical concentrations)

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

Five groups consisting of five male and five female Sprague-Dawley rats per group were exposed to an atmosphere containing the test subtance for four hours. All survivors were held for a 14-day post-exposure observation period.
A gross necropsy examination was performed on all animals dying spontaneously during the study and on all survivors at the end of the 14-day post-exposure observation period.
A control group also consisting of five male and five female Sprague-Dawley rats was included. These animals received a four-hour exposure to house-supply air only.

In-Life Observations:
Day 1 (Day of Exposure): All animals were observed individually prior to exposure, as a group at approximately fifteen minute intervals during the first hour of exposure, each one-half hour for hours 1 through 2 and hourly for the remainder of the exposure. All survivors were observed individually upon removal from the chamber (half-hour after exposure was completed) and 4 hours post-exposure. Detailed physical observations were recorded at each interval.
Days 2 through 15 (Post-exposure): Detailed observations were recorded for survivors once dailyl; viability was assessed twice daily.

Body Weight:
Day 1 (immediately prior to exposure) and on Days 2, 3, 4, 8, 11 and 15.

Postmortem:
A necropsy was performed on all animals dying spontaneously or sacrificed at the end of the post-exposure observation period. The gross postmortem examinations included the nasal passages, trachea, external surface, all orifices, the cranial cavity, carcass, the brain and spinal cord, the thoracic, abdominal and pelvic cavities and their viscera and the cervical tissues and organs.

Statistics:

A calculation of median lethal concentration and 95% confidence limits was performed according to the method of Litchfield and Wilcoxon.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

6 270 other: ppm (analytical)

95% CL:

5 180 - 7 590

Exp. duration:

4 h

Remarks on result:

other: = 22572 mg/m3

Sex:

male/female

Dose descriptor:

other: LOAEC for local irritation

Effect level:

3 090 ppm

Exp. duration:

4 h

Remarks on result:

other: = 11142 mg/m3. Lacrymation, nasal discharge and respiratory distress

Mortality:

Chamber Monitoring and Mortality:
The mean analytical and nominal exposure concentrations of tetrahydrothiophene along with the overall mortality in each test group are summarized as follows:

Mean Mean
Analytical Nominal
Group Concentration Concentration Mortality
(ppm) (ppm) #dead/#exposed
Male female
I 6300 9480 5/5 5/5
II-Control 0 0 0/5 0/5
III 3090 5460 0/5 0/5
IV 4400 6060 0/5 0/5
V 5260 8330 2/5 0/5
VI 5670 8170 1/5 1/5

The analytical concentrations were approximately two thirds of the nominal exposure concentrations. No reason for these differences was found. No aerosol was found during any exposure. The distribution of material in chamber was acceptable.

Based on the mean analytical concentration values of tetrahydrothiophene and resultant mortality, the LC50 values and 95% confidence limits were calculated to be:

Sex LC50 95% Confidence Limits
ppm
Combined Sexes
(males and females) 6270 5180 to 7590
Males 5900 4960 to 7010
Females 6700 5540 to 8100

Clinical signs:

other: 1. Exposure Period: Most animals exposed to 6300 ppm tetrahydrothiophene died during exposure. Lacrimination, respiratory distress, reduced activity, matted coat, prostration and poor condition were exhibited by these animals. Similar signs, except deat

Body weight:

Male body weights decreased or exhibited stasis through Day 3. Subsequently, increments for male body weight gain were normal (except at 5670 ppm between Days 8 and 11). In females, body weights decreased between Days 1 and 2. Subsequent female body weight gain increments were normal (except at 5260 and 5670 ppm in the periods 11-15 days and 8-11 days respectively). During the second week post-exposure, at 4400 and 5260 ppm, female body weight gains were decreased compared to control animals. These effects were considered treatment related. Second week post-exposure body weights for other groups were considered unremarkable.

Gross pathology:

A number of the tissues and organs for the animals which died during the study were discolored, primarily red, of various intensities. This finding was not considered to be unusual in animals which died and were not exsanguinated prior to postmortem examination.
The toxicological significance, if any, with respect to the test article, of the dark red lungs observed in the animals which died during the study, remains equivocal. The lungs of the animals which survived to the end of the study exhibited various discolorations which were observed in a number of the animals of all groups. These, and other findings which occured sporadically in the animals of this study, were not considered to be related to the test article.

Interpretation of results:

GHS criteria not met

Conclusions:

A series of groups consisting of five male and five female Sprague-Dawley rats was exposed to tetrahydrothiophene vapors for four hours at mean analytical levels in the range of 3090 to 6300 ppm. The resultant median lethal concentration values were 6270 ppn for the combined sexes, 5900 ppm for males and 6700 ppm for females. This suggested that the test material was of comparable toxicity to both sexes.
Signs attributable to treatment included death, increased incidences of secretory responses, respiratory distress, reduced activity, matted coat, prostration, poor condition, ano-genital area staining and loss of body weight. Overall, the time-to-onset and time-to-recovery of these signs appeared to be related to exposure concentration.
Gross postmortem evaluations revealed darken, reddish lungs for decedents. The toxicological significance of this finding, if any, remains equivocal.

Executive summary:

A series of groups consisting of five male and five female Sprague-Dawley rats was whole-body exposed to tetrahydrothiophene vapors for four hours at mean analytical levels in the range of 3090 to 6300 ppm (11142 to 22718 mg/m³). The study was performed according to EPA guideline #OPP 81-3 and GLP (Terrill, 1986). Signs attributable to treatment included death, increased incidences of secretory responses, respiratory distress, reduced activity, matted coat, prostration, poor condition, ano-genital area staining and loss of body weight. Overall, the time-to-onset and time-to-recovery of these signs appeared to be related to exposure concentration. The resultant median lethal concentration values were 6270 ppm (22572 mg/m³) for the combined sexes.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

22 572 mg/m³

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Qualifier:

according to guideline

Guideline:

EPA OTS 798.1100 (Acute Dermal Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hazleton-Dutchland, Inc., Denver, PA
- Age at study initiation: at least 8-week old
- Weight at study initiation: 2.6-2.9 kg for males and 2.5-3.1 kg for females- Fasting period before study:
- Housing: individually in stainless steel cages
- Diet (e.g. ad libitum): Lab Rabbit Chow HF, Purina #5326
- Water (e.g. ad libitum): tap water
- Acclimation period: 21 days

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 60-70
- Humidity (%): 30-70
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

Preparation of Animals:
On the day before dosing the hair of each rabbit was closely clipped from the trunk (dorsal and ventral surface and sides from scapular to pelvic area) with an electric clipper, so as to expose at least 10% of the body surface area. The skin remained intact, no abrasions were made.

Administration of Test Material:
The material was applied directly onto the exposed skin of the animal, and spread evenly over the entire area. Gauze was then wrapped around the animal to cover the application site. The animal was then wrapped in an impervious plastic sleeve, designed to contain the test material without leakage or undue pressure. The sleeve was secured with tape and Elizabethan collars were placed on all animals to prevent ingestion of the test material or disruption of the wrappings.
Following approximately 24 hours of exposure, the wrappings were removed and the test site wiped free of excess test material.

Duration of exposure:

24 hours

Doses:

2000 mg/kg

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

A single dose was administered to each animal, followed by 14 days of observations.

EXPERIMENTAL EVALUATION
Viability Check: Twice Daily

Observations of Pharmacologic and Toxicologic Signs:
Approximately 1, 2 and 4 hours after dosing and daily thereafter for fourteen days

Body Weights:
Pre-test, at the time of clipping (weights used for calculation of doses)
Days 7 and 14

POSTMORTEM
All animals surviving at termination of the observation period (Day 14) were killed by an intravenous overdose of sodium pentobarbital and examined grossly. All abnormalities were recorded but no tissues were saved.

Statistics:

None

Sex:

male/female

Dose descriptor:

LD0

Effect level:

> 2 000 mg/kg bw

Mortality:

All animals survived throughout the study. Therefore, the dermal LD0 of Tetrahydrothiophene in rabbits is greater than 2000 milliqrams per kilogram of body weight.

Clinical signs:

Most animals exhibited severe dermal effects at the dose site (necrosis followed by eschar formation, fissuring and/or exfoliation of the eschar tissue) which persisted throughout the study.
Most animals exhibited hyperpnea on the day of dosinq. Other signs seen in one or two animals on the day of dosing included fine tremors, nasal discharge, dyspnea, arythmic respiration and red eyes. Several animals were noted to have decreased food consumption on Days 1, 2 and/or 3. This may represent an effect of test material administration or it may be related to some difficulties which were encountered with the water supply on Day 2 (low pressure) and Day 3 (temporary discontinuation of water to females). Most animals were free of significant signs of toxicity from Day 4 through study termination (Day 14), although two animals exhibited mucoidal stool and/or decreased food consumption between Days 10 and 13.

Body weight:

Most animals exhibited slight body weight losses at Day 7, but most gained weight between Days 7 and 14. One male exhibited a continuous weight loss over the study.

Gross pathology:

Gross postmortem observations confirmed the presence of dermal lesions discussed previously. Unusual observations included surface irregularities (wrinkling) of the spleen in five animals, discolored kidneys (mottled tan) in three animals and fissures in the liver in two animals. Other observations were similar to those seen in control animals in this laboratory or were considered to represent normal physiological variation.

Interpretation of results:

GHS criteria not met

Conclusions:

The dermal LD0 of Tetrahydrothiophene in rabbits is greater than 2000 mg/kg body weight.

Executive summary:

In an acute dermal toxicity study performed according to EPA guideline #OTS 798.1100 and GLP, Tetrahydrothiophene was administered to male and female New-Zealand rabbits at the dose level of 2000 mg/kg. All animals survived throughout the study. Most animals exhibited severe dermal effects at the dose site (necrosis followed by eschar formation, fissuring and/or exfoliation of the eschar tissue) which persisted throughout the study. Most animals exhibited hyperpnea on the day of dosinq. Other signs seen in one or two animals on the day of dosing included fine tremors, nasal discharge, dyspnea, arythmic respiration and red eyes. Gross postmortem observations confirmed the presence of dermal lesions discussed previously. Unusual observations included surface irregularities (wrinkling) of the spleen in five animals, discolored kidneys (mottled tan) in three animals and fissures in the liver in two animals. The dermal LD0 of Tetrahydrothiophene in rabbits is greater than 2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Justification for classification or non-classification

In accordance with Regulation (EC) No 1272/2008, THT shall be classified as Acute Tox. 4 (Hazard statement: H302; Harmful if swallowed).