Tetrahydrofurfuryl alcohol

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1994-10-03 to 1995-01-26

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1998

Report date:

1998

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Tetrahydrofurfuryl alcohol

EC Number:

202-625-6

EC Name:

Tetrahydrofurfuryl alcohol

Cas Number:

97-99-4

Molecular formula:

C5H10O2

IUPAC Name:

tetrahydrofuran-2-ylmethanol

Test material form:

other: liquid

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 Labs, Portage, MI, USA
- Age at study initiation: 6 wk
- Weight at study initiation: 155-203 (m); 129-159 (f) g
- Fasting period before study: no data
- Housing: 1/wire mesh cage
- Diet: standard diet at libitum
- Water: drinking water ad libitum
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72 +/- 4 deg F
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12 h/12 h

IN-LIFE DATES: From: To: 1994-10-03 to around 1995-01-03

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

clean air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 0.5 m3 stainless steel and glass inhalation chambers, dynamic operation
- Source and rate of air: filtered air, 12-15 chamber volumes/hr
- Temperature, humidity, pressure in air chamber: 19.7-25.8 deg C; 19-85 % RH
- Air change rate: 12-15 chamber volumes/hr

TEST ATMOSPHERE
- Brief description of analytical method used: infrared spectoscopic method , examination 3 times daily (no findings given in Volumer 1 of report)

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

6 hr/day, 5 days/wk, at least 65 exposures (equivalent to 13 weeks)

Frequency of treatment:

daily on weekdays

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

50 ppm (nominal)

Doses / concentrations 2

Dose / conc.:

150 ppm (nominal)

Doses / concentrations 3

Dose / conc.:

500 ppm (nominal)

No. of animals per sex per dose:

10, with a further 4 males per concentration to examine spermatogenic effects

Control animals:

yes, concurrent vehicle

Positive control:

no

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice per day

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once/week

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: weeks 0 and 12

HAEMATOLOGY: Yes
- Time schedule for collection of blood: weeks 3, 13
- Anaesthetic used for blood collection:No data
- Animals fasted: Yes
- How many animals: all survivors from main groups (10/sex/concentration)
- Parameters checked in table 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
- Animals fasted: Yes
- How many animals: all survivors from main groups (10/sex/concentration)
- Parameters checked in table 1 were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: examination of groups of 4 males at week 6 and 10 males at week 13, at each concentration, for effects on spermatogenic endpoints

Sacrifice and pathology:

GROSS PATHOLOGY: Yes see table 2
HISTOPATHOLOGY: Yes see table 2

Statistics:

2-tailed tests for minimum significance levels of 1% and 5%, comparing treatment groups to the vehicle control. Body weight, weight change, food consumption, clinical laboratory, spermatogenic and organ weight data were subjected to a 1-way analysis of variance and Dunnett’s 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

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

no effects observed

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

Description (incidence and severity):

testis

Details on results:

CLINICAL SIGNS AND MORTALITY
1/10 females died in at 50 ppm during week 0, the cause of death was not found to be treatment-related. The predominant clinical finding was intermittent whole-body spasms in all treated groups that were frequent and exposure-related. Hypoactivity and excessive grooming were occasionally observed in males and females at 500 ppm. One hour after exposure, concentration-related hyperactivity was reported in all treated groups, and yellow urogenital matting and salivation at 500 ppm.

BODY WEIGHT AND WEIGHT GAIN
Mean body weight gains were lower than controls in males at 150 and 500 ppm (9.2% and 13.3%, respectively).

FOOD CONSUMPTION
Mean food consumption was generally lower in mid and high exposure males throughout the study

OPHTHALMOSCOPIC EXAMINATION
No treatment-related observations.

HAEMATOLOGY
Several statistically significant treatment-related changes were reported after exposure to 500 ppm. Platelet and haemoglobin means were significantly reduced in both sexes (study weeks 3 and/or 13). MCH (mean cell haemoglobin) was reduced in males (weeks 3 and 13) and females (week 13); MCHC (mean corpuscular haemoglobin concentration) was reduced in males (week 13) and females (week 3).

CLINICAL CHEMISTRY
No treatment-related effect.

ORGAN WEIGHTS
Prostate weight (absolute and relative) were lower than controls in 150 and 500 ppm groups. The weights of seminal vesicles (absolute) and epididymides (absolute and relative) were lower at 500 ppm.

GROSS PATHOLOGY
No macroscopic lesions in any exposure group.

HISTOPATHOLOGY: NON-NEOPLASTIC
Spermatogenic findings: reduced epididymal sperm numbers and motility, and a higher incidence of morphological abnormalities were seen in 500 ppm males at weeks 6 and 13. Multifocal atrophy of the testes was reported in a single male at 500 ppm.

Effect levels

1

Dose descriptor:

NOAEC

Effect level:

50 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: whole body spasm and hyperactivity, and other effects.

Remarks on result:

not determinable

Remarks:

no NOAEC identified

2

Dose descriptor:

LOAEC

Effect level:

50 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: around 0.2 mg/l

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

A well reported 90-day rat inhalation study, conducted according to the current guideline and in accordance with GLP, did not identify a NOAEC value. Clinical observations (including spasm) were evident at the lowest tested nominal concentration of 50 ppm (around 0.2 mg/l).