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Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1992-02-19 to 1993-01-25
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report date:
1993

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Principles of method if other than guideline:
No guideline stated, broadly similar to OECD 408.
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:
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: approx 23 days
- Housing: 1/wire mesh cage
- Diet: standard diet (Purina Certified Rodent Chow #5002
- Water: drinking water ad libitum
- Acclimation period: 20 days, including pretest

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 67-75 deg F
- Humidity (%): 29-88 (said not to have affected results)
- Air changes (per hr): 12h/ 12h
- Photoperiod (hrs dark / hrs light):

IN-LIFE DATES: From: 1992-02-19 To: 1992-05-22

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: standard diet
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): diet offered fresh weekly


Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Three samples were taken from the 500 and 10,000 ppm diets to determine homogeneity, stability (for 7 and 14 days). Samples were taken from the middle of each control and test diet on the day of preparation during weeks 0, 1, 2, 3, 7 and 12 to determine concentration of test substance.

Individual food consumption was measured weekly and the mean daily dose calculated for each dose group using body weight.
Duration of treatment / exposure:
91-93 days
Frequency of treatment:
diet ad libitum
Doses / concentrationsopen allclose all
Dose / conc.:
35 mg/kg bw/day (actual dose received)
Remarks:
males: equivalent to 500ppm
Dose / conc.:
69 mg/kg bw/day (actual dose received)
Remarks:
males: equivalent to 1000ppm
Dose / conc.:
339 mg/kg bw/day (actual dose received)
Remarks:
males: equivalent to 5000ppm
Dose / conc.:
673 mg/kg bw/day (actual dose received)
Remarks:
males: equivalent to 10000ppm
Dose / conc.:
42 mg/kg bw/day (actual dose received)
Remarks:
females: equivalent to 500ppm
Dose / conc.:
84 mg/kg bw/day (actual dose received)
Remarks:
females: equivalent to 1000ppm
Dose / conc.:
401 mg/kg bw/day (actual dose received)
Remarks:
females: equivalent to 5000ppm
Dose / conc.:
781 mg/kg bw/day (actual dose received)
Remarks:
females: equivalent to 10000ppm
No. of animals per sex per dose:
20
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale:
- Rationale for animal assignment: computer randomized
Positive control:
no

Examinations

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

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly (from wk -1)

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to treatment and week 12
- Dose groups that were examined: all groups

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at necropsy (13 wk)
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: 10/sex/dose
- Parameters checked in table No.1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
- Animals fasted: Yes
- How many animals: 10/sex/dose
- Parameters checked in table No.1 were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (see table 2)
Statistics:
All analyses were conducted using 2-tailed tests for minimum significance levels 1% and 5% comparing treated groups with controls by sex. Body weights, food consumption, clinical laboratory parameters, absolute and relative organ weights: 1-way analyis of variance and Dunnett's test.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
no deaths, rectal mucous exudate.
Mortality:
mortality observed, treatment-related
Description (incidence):
no deaths, rectal mucous exudate.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
significant reduction in final body weight in males at 1000 ppm and above and in females at 5000 ppm and above
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
reduced food consumption at 5000 ppm in males and 10000 ppm in both sexes
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
dose-related effects at 5000 ppm and above in both sexes
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
dose-related effects at 5000 ppm and above in both sexes
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
lower testis, epididimal and prostate weight (5000 and/or 10,000 ppm)
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
testis: small and/or soft at 5000 ppm and above
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
testis: dose-related degenerationof germinal epithelium of seminiferous tubules and interstitial oedema at 5000 ppm and above. Adhesions of the spleen at these doses and capsular fibrosis (focal) sporadically in all treated groups.
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
No deaths.
Rectal mucous exudate sporadically at 5000 ppm and above.

BODY WEIGHT AND WEIGHT GAIN
Significant reduction in final body weight in males at 1000 ppm and above and in females at 10,000 ppm (p<0.01 in both cases). Dose-related decreases (statistically significant in some cases) in mean body weights (compared to control) and body weight gains in all treated male groups (500 ppm and above) and in females in the top two dose groups.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Reduced food consumption at 5000 ppm in males and 10,000 ppm in both sexes. Dose-related decrease in mean food consumption in treated male groups.

OPHTHALMOSCOPIC EXAMINATION
No treatment-related effects.

HAEMATOLOGY
Dose-related effects at 5000 ppm and above in both sexes: decreased haemoglobin, MCH, MCHC and platelet counts. Slightly reduced MCV values in females at 5000 ppm and above.

CLINICAL CHEMISTRY
Dose-related effects at 5000 ppm and above in both sexes: dose-related reduction in total protein and globulin, and increased A/G ratio at 5000 ppm and above in both sexes. Albumin was reduced in females at 10,000 ppm.

ORGAN WEIGHTS
Reduced testis and epididimal weight (mean absolute and relative) at 5000 ppm and above in males, lower prostate weight (mean absolute and relative) at 10,000 ppm (all p<0.01 or 0.05, except mean relative testis weight at 5000 ppm). Absolute seminal vesicle weights were lower at 5000 ppm and above, and absolute prostate weight was lower at 1000 and above. Differences in liver weights were not considered treatment-related due to inconsistency between the responses of the sexes. No other treatment-related differences reported.

GROSS PATHOLOGY
Testis: small and/or soft at 5000 ppm and above

HISTOPATHOLOGY: NON-NEOPLASTIC
Testis: dose-related degeneration of germinal epithelium of seminiferous tubules and interstitial (peritubular) oedema at 5000 ppm and above.
Epididymides: empty or fluid filled tubules with accumulation of cellular debris seen in all 10,000 ppm males and some 5000 ppm males.
Spleen: adhesion to mesentery, abdominal wall or adipose tissue sporadically at 5000 ppm and above (both sexes). Capsular fibrosis (focal) sporadically in all treated groups. The investigators noted that while this effect may have been treatment-related its toxicological significance was not known.

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
500 ppm
Based on:
other: in the diet
Sex:
male
Basis for effect level:
other: mean measured dose 35 mg/kg bw/day
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 ppm
Based on:
other: in the diet
Sex:
female
Basis for effect level:
other: mean measured dose 84 mg/kg bw/day

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
A well reported 90-day dietary study, conducted in the main according to the current guideline and in accordance with GLP, identified NOAELs of 500 ppm and 1000 ppm in the diet in male and female rats, respectively. This dietary intake was equivalent to mean measured intakes of 35 and 84 mg THFA/kg bw/day, in males and females. Reduced body weights were reported at the next highest dietary concentration in both cases. The testis was the major target organ.