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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
The inhalation toxicity of sulfolane (tetrahydrothiophene-1,1-dioxide).
Author:
Andersen, ME, Jones, RA, Mehl, RG, Hill, TA, Kurlansik, L, and Jenkins, Jr, LJ
Year:
1977
Bibliographic source:
Toxicology and Pharmacology 40: 463-472.

Materials and methods

Principles of method if other than guideline:
No further information is available.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): sulfolane
- Analytical purity: not stated
- Minor constituent: 3% water (added to prevent freezing)

Test animals

Species:
guinea pig
Strain:
Hartley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 295 – 460 g
- Diet: Commercial prepared dry chow ad libitum except during exposure
- Water: ad libitum except during exposure.

IN-LIFE DATES: From:

Administration / exposure

Route of administration:
other: inhalation, aerosol (200, 159 and 20 mg/m3 exposure concentrations); inhalation, gas (4.0 and 2.8 mg/m3 exposure concentrations)
Type of inhalation exposure:
whole body
Vehicle:
other: water
Remarks on MMAD:
MMAD / GSD: No information is available.
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Rochester-type chambers were used for the whole body exposures. Airflow was maintained at 1 m3/min with constant temperature (25 + 1oC) and relative humidity (50%).

For the three highest exposure concentrations, sulfolane was pumped from a reservoir into a high-pressure spray nozzle, dispersed into an aerosol, pumped through laminar flow tubing and a drum impactor, and diluted with input air before entering into the chamber. Input concentration could be varied by altering the amount of sulfolane to the aerosolizer, by changing the pressure at the spray nozzle, and the amount of sulfolane in the reservoir with distilled water.

At the two lower exposure concentrations, air was bubbled through a sulfolane solution and then mixed with chamber input air. Concentrations were adjusted by changing the flow rate of air into the reservoir. Since sulfolane freezes at 27.5oC, the reservoir and input lines were wrapped with heat tape and maintained above room temperature. Exposure was discontinued for approximately one hour each day to feed the animals.

TEST ATMOSPHERE
Atmospheric sulfolane concentrations were determined by drawing known volumes of chamber air first through an impinger and then through a bubbler containing distilled water. The aerosolized sulfolane trapped by the impinger was dissolved in distilled water. Sulfolane in these aqueous solutions was determined by gas-liquid chromatography with flame ionization detection. Samples were taken every 6 hours during the exposures.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
No information is available.
Duration of treatment / exposure:
90-110 days (90, 85, 95, 110, and 90 days for the 200, 159, 20, 4.0 and 2.8 mg/m3 exposure concentrations, respectively)
Frequency of treatment:
23 hours/day, 7 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
2.8 mg/m³ air (analytical)
Remarks:
+1.4
Dose / conc.:
4 mg/m³ air (analytical)
Remarks:
+1.0
Dose / conc.:
20 mg/m³ air (analytical)
Remarks:
+6.7
Dose / conc.:
159 mg/m³ air (analytical)
Remarks:
+68
Dose / conc.:
200 mg/m³ air (analytical)
Remarks:
+48
No. of animals per sex per dose:
15 animals/sex for the 200 mg/m3 group; 24 animals/sex for the 159 mg/m3; 8 males and 7 females for the 20 mg/m3 group; 15 males/group for the 4.0 and 2.8 mg/m3 groups.
Control animals:
yes, sham-exposed
Positive control:
None

Examinations

Observations and examinations performed and frequency:
Effects on general toxicity, hematology, clinical chemistry, and urinalysis were evaluated.
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: no data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: no data

BODY WEIGHT: Yes
- Time schedule for examinations: prior to exposure; after 30 and 60 exposure-days; and at study termination.

FOOD CONSUMPTION: No

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 30 and 60 exposure days, and at study termination (also at 20 exposure days for the 200 mg/m3 group only).
- Anaesthetic used for blood collection: no data, except at termination (lethal dose of pentabarbital)
- Animals fasted: no data
- How many animals: 5 animals/sex per timepoint for the 200, 159, 20, 4.0 and 2.8 mg/m3 dose groups; 8 males and 7 females for the 20.0 mg/m3 dose group. In addition, 8 males and 2 females were bled after 20 exposures in the 200 mg/m3 group.
- Parameters examined: total and differential leucocyte counts, hemoglobin concentrations, and hematocrit.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 30 and 60 exposure days, and at study termination.
- Anaesthetic used for blood collection: Yes (lethal dose of pentabarbital)
- Animals fasted: Yes
- How many animals: 5 animals/sex per timepoint for the 200, 159, 20, 4.0 and 2.8 mg/m3 dose groups; 8 males and 7 females for the 20.0 mg/m3 dose group.
- Parameters examined: creatinine, urea nitrogen, cholesterol concentrations; alkaline phosphatase, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase activity.

URINALYSIS: Yes
- Time schedule for collection of urine: At study termination.
- Metabolism cages used for collection of urine: no data
- How many animals: 5 animals/sex for the 200, 159, 20, 4.0 and 2.8 mg/m3 dose groups; 8 males and 7 females for the 20.0 mg/m3 dose group.
- Parameters examined: estimation of pH, protein, sugar, ketone bodies, and occult blood.

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: No data
ORGAN WEIGHTS: No data
HISTOPATHOLOGY: Yes. Tissues examined: lung, bronchus, heart, kidney, bile duct, liver, spleen, stomach, intestine, pancreas, cerebellum, esophagus, thyroid, trachea, lymph node, bladder and aorta.
Other examinations:
None
Statistics:
A students t-test was used.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
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:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
HAEMATOLOGY
White blood cell counts were significantly lower in the 200 mg/m3 group at exposure days 20, 30 and at study termination.

CLINICAL CHEMISTRY
No effects considered to be treatment-related.

GROSS PATHOLOGY
In the 200 mg/m3 group, several of the livers appeared fatty.

HISTOPATHOLOGY: NON-NEOPLASTIC
200 mg/m3: all of the guinea pigs in the 30-day termination group had chronic pleuritis. Histopathogical examination of the liver showed that 4/5 animals at day 30, 6/7 at day 60, and 4/5 at study termination had fatty vacuolization.

Effect levels

open allclose all
Key result
Dose descriptor:
LOAEC
Effect level:
200 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Leukopenia; hemorrhagic, inflamed lungs; fatty vacuolation of the liver.
Key result
Dose descriptor:
NOAEC
Effect level:
159 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
haematology
gross pathology
histopathology: non-neoplastic

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Guinea pigs were exposed by inhalation to sulfolane either as a vapor/aerosol (20, 159 or 200 mg/m3) or as a vapor (2.8 and 4.0 mg/m3) for 90-110 days. At 200 mg/m3, animals exhibited chronic pleuritis, leukopenia (decreased white blood cells), and fatty vacuolization of the liver. At 159 mg/m3 or lower, there were no treatment-related effects. A NOAEC of 159 mg/m3 was established.
Executive summary:

Guinea pigs were exposed by inhalation to sulfolane either as a vapor/aerosol (20, 159 or 200 mg/m3) or as a vapor (2.8 and 4.0 mg/m3) for 90-110 days. At 200 mg/m3, animals exhibited chronic pleuritis, leukopenia (decreased white blood cells), and fatty vacuolization of the liver. At 159 mg/m3 or lower, there were no treatment-related effects. A NOAEC of 159 mg/m3 was established.