Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1994-09-08 to 1994-12-15
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 411 (Subchronic Dermal Toxicity: 90-Day Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Tetrahydrofurfuryl alcohol
EC Number:
202-625-6
EC Name:
Tetrahydrofurfuryl alcohol
Cas Number:
97-99-4
Molecular formula:
C5H10O2
IUPAC Name:
(oxolan-2-yl)methanol
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
- Weight at study initiation g: 168-209 (m); 137-164 (f)
-age: 6 weeks
- Housing: 1/ wire mesh cage
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 70-76 deg F
- Humidity (%): 37-66
- Photoperiod (hrs dark / hrs light): 12 h/12 h

IN-LIFE DATES: From: To: 1994-09-15 to 1994-12-15

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure:
- % coverage: 20-25% shaved; coverage (maximum possible) 1.7-4.1% and 1.6-4.2% coverage of body for males, and females, respectively
- Type of wrap if used: gauze binder, impervious plastic wrap, dermiform tape
- Time intervals for shavings or clipplings: day prior to dosing and weekly

REMOVAL OF TEST SUBSTANCE
- Washing (if done): wiped with wet paper towel moistened with tepid tap water
- Time after start of exposure: 6h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.095, 0.29, 0.96 ml/kg bw/day; 100, 300, 1000 mg/kg bw/day
- Concentration: neat
- Constant volume or concentration used: no

VEHICLE
Control: 0.9% saline, 0.95 ml/kg bw/day

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes (Elizabethan restraint collars)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
application neat; purity reported
Duration of treatment / exposure:
6h/day, 5 days/week, 13 weeks
Frequency of treatment:
daily (weekdays)
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day
Remarks:
analytical per unit body weight
Dose / conc.:
300 mg/kg bw/day
Remarks:
analytical per unit body weight
Dose / conc.:
1 000 mg/kg bw/day
Remarks:
analytical per unit body weight
No. of animals per sex per dose:
17 males, 12 females (5 males terminated at 7 weeks for examination of spermatogenic endpoints)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
- Rationale for animal assignment (if not random): computer randomization
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: weekly

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

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule: week 12
- slit lamp and indirect ophthalmoscope

HAEMATOLOGY: Yes
- Time schedule for collection of blood: weeks 4, 13
- Anaesthetic used for blood collection: /No data
- Animals fasted: Yes
- How many animals: 12/sex/dose
- Parameters checked in table 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: weeks 4, 13
- Animals fasted: Yes
- How many animals: 12/sex/dose
- Parameters checked in table 1 were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER:

Spermatogenic endpoints: 5 males/dose; terminated at week 7: sperm motility, morphology
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table 2)
HISTOPATHOLOGY: Yes (see table2)
Statistics:
All analyses were conducted using two-tailed tests for significance levels of 5 % and 1%.
Body weight, body weight change, food consumption, clinical laboratory, spermatogenic and absolute and relative organ weight data were subjected to a one-way analysis of variance followed by Dunnett's Test. Clinical laboratory values for white blood cell types that occur at a low incidence (i.e. monocytes, eosinophils, basophils and unsegmented neutrophils) were not subjected to statistical analysis.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
very minimal dermal irritation
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
reduced mean body weight in both sexes at 1000 mg/kg bw/day
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:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
No mortatily or treatment-related clinical signs.

BODY WEIGHT AND WEIGHT GAIN
8-10% lower weight gain in 1000 mg/kg bw/day males comapred to controls (p<0.05 or 0.1; weeks 9-13). 7% lower weight gain in 1000 mg/kg bw/day females compared to controls (p<0.05; weeks 12, 13).

FOOD CONSUMPTION
No effect.

OPHTHALMOSCOPIC EXAMINATION
No treatment-related effects at week 12 examination.

HAEMATOLOGY
No treatment-related effect on haematological parameters. Mean white blood cell counts and absolute numbers of lymphocytes were lower (p<0.01 or 0.05) in 1000 mg/kg bw/day males at weeks 4 and 13 examinations, No similar effects were seen in females and the white cell counts were within WIL Research Laboratories historic control ranges for this species, strain and age. Statistically significant differences in red blood cell parameters did not show trends to indicate they were treatment-related.

CLINICAL CHEMISTRY
No treatment-related effect on serum chemistry parameters. Statistically significant differences (p<0.01 or <0.05) in serum protein parameters were seen in both sexes at 1000 mg/kg bw/day at weeks 4 or 13 but these were small, their means within the normal range of biologic variation and without trend to indicate an association with treatment. Other statistically significant differences were limited to one sex at a single evaluation, showed no dose-response or were not considered toxicologically significant.

ORGAN WEIGHTS
No treatment-related effect.

GROSS PATHOLOGY
No treatment-related observations.

HISTOPATHOLOGY: NON-NEOPLASTIC
No treatment-related effects at any dose including effects on skin and male reproductive organs

OTHER FINDINGS
dermal: very limited dermal irritation - single occasions of very slight erythema for one, two and one males in the 100, 300 and 1000 mg/kg bw/day groups, respectively, and or one female in the 100 mg/kg bw/day group. Desquamation was observed on one day for single females in the control and 100 mg/kg bw/day group and thus was apparently not test article-related. No other dermal irritation was observed.

Spermatogenic endpoints:
Administration of up to 1000 mg THFA/kg bw/day for 7 weeks (interim necropsy) had no effect on spermatogenic endpoints (testicular epididymal sperm numbers, sperm production rate, sperm motility, sperm morphology).

Mean numbers of sperm present in testicular homogenates and mean sperm production rate were lower than controls in 300 and 1000 mg/kg bw/day males after 13 weeks treatment (p<0.01). One male in the 1000 mg/kg bw/day group had markedly lower values for these parameters but the the group mean was still significantly reduced (p<0.01) when the values for this male were omitted. Sperm motility was reduced at 1000 mg/kg bw/day (p<0.05).

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: spermatogenesis
Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: lower body weight gain

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
A 90-day dermal study, conducted according to the current guideline (OECD 411) and GLP, identified NOAEL values of 100 mg/kg bw/day in male rats and 300 mg/kg bw/day female rats. Effects on body weight were evident at 1000 mg/kg bw/day in both sexes and spermatogenic effects were reported in males at 300 mg/kg bw/day.