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Administrative data

Endpoint:
short-term repeated dose 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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2000
Report date:
2000

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes

Test material

Constituent 1
Reference substance name:
(3-Aminomethyl)tetrahydrofuran
IUPAC Name:
(3-Aminomethyl)tetrahydrofuran
Test material form:
other: liquid
Details on test material:
- Name of test material (as cited in study report): (3-Aminomethyl)tetrahydrofuran
- Physical state: clear liquid
- Analytical purity: 99.8 %
- Lot/batch No.: MAP 61-068

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 Japan Inc, Atsugi Breeding Center
- Age at study initiation: 6 - 7 weeks
- Weight at study initiation: 223 - 255 g (males); 169 - 194 g (females)
- Housing: individually
- Diet (e.g. ad libitum): ad libitum (irradiation sterilized CRF-1, Oriental Yeast Co., Ltd.)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 9 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 25 °C
- Humidity (%): 40 - 70 %
- Air changes (per hr): 10 to 15 times per hour
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: For each concentration, the test article was measured with a graduated pipette or an autopipette (specific gravity of the test article was regarded as 1 g/mL) and dissolved in the vehicle (water for injection, JP, Otsuka Pharmaceutical Factory lnc., Lot No. 9K77) to prepare test solutions at 1.2, 6 and 30 v/v%. The test solutions were prepared at least once every 8 days.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis of the test solutions of each concentration used in weeks 1 and 4 of administration by the HPLC method at Gotemba Laboratory, Bozo Research Center
lnc. revealed that the concentrations of the test article in test solutions were between 98.7 and 103.3% of the nominal values and were within the permissible
range (nominal value +/- 10%). Analysis of the test solutions by the HPLC method at Gotemba Laboratory, Bozo Research Center Inc. revealed that the test article was stable in test solutions at concentrations from 0.5 to 100 v/v% for 8 days in a refrigerator (1·8°C) plus 3 hours at room temperature (permissible limit: decrease by not more than 10% of the initial value).
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 12, 60, 300 mg/kg
Basis:

No. of animals per sex per dose:
10 males and females in control and 300 mg/kg group (5 males and females as 14 days recovery group)
5 males and females in the 12 and 60 mg/kg group
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed for general condition 3 times - prior to, immediately after and 2 hours after dosing (but twice on Saturdays and holidays prior to and immediately after dosing) - every day during the administration period and once daily (in the moming) during the recovery period.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: For all animals, the following examinations were done once before the start of administration, and once weekly during the administration and recovery periods. Home cage observation, in the hand observation, Open field observation, functional observation battery and motor activity were measured.

BODY WEIGHT: Yes
- Time schedule for examinations: brfore dosing, days 1,4,and 7 of administration and twice weekly, every 3 or 4 days, thereafter.

FOOD CONSUMPTION AND COMPOUND INTAKE : On day 1 of administration, one day's food consumption from the day previous to administration was recorded before dosing of the day. Thereafter, one day's food consumption during the administration period was calculated from 3 or 4 days' cumulative consumption recorded before dosing of the day.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: One day's water intake was measured using a water bottle while each animal was housed in a cage equipped with a urine collector.

HAEMATOLOGY: Yes

CLINICAL CHEMISTRY: Yes

URINALYSIS: Yes
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Bartletts test, Dunnett`s test, F-test, Student`s t-test, Aspin-Welch`s t-test,an Mann-Whitney`s u-test

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
Administration period : There were neither deaths nor treatment-related clinical signs in males or females. At 300 mg/kg, wheezing, which was thought to be caused by irritation of the test article, was observed in a few males, and wheezing, unkempt fur and emaciation were observed in a few females.
Recovery period: No deaths occurred.

BODY WEIGHT AND WEIGHT GAIN
There were no treatment-related effects. (Administration period and Recovery period)

FOOD CONSUMPTION AND COMPOUND INTAKE
There were no treatment-related effects. (Administration period and Recovery period)

OPHTHALMOSCOPIC EXAMINATION

HAEMATOLOGY
There were no treatment-related effects.

CLINICAL CHEMISTRY
There were no treatment-related effects.

URINALYSIS
At 300 mg/kg, changes observed were an increase in urinary protein in males and females, increases in urobilinogen and phosphate crystals in sediment, a decrease in urine volume, and elevated osmotic pressure in males and an increase in glucose in females. At 60 mg/kg, changes observed were increases in urinary protein and phosphate crystals in Sediment and a decrease in urine volume in males.

ORGAN WEIGHTS
There were no treatment-related effects.

GROSS PATHOLOGY
At 300 mg/kg, gross pathological changes observed were thickening of limiting ridge in the stomach and focal dark reddening of the glandular stomach in males and females.

HISTOPATHOLOGY
At 300 mg/kg, changes observed were thickening of limiting ridge in the stomach, and mucosal hemorrhage and erosion/healed erosion in the glandular stomach in males and females, and mucosal thickening in the forestomach and cell infiltration sinusoid in the Iiver in females.
At 60 mg/kg, thickening of limiting ridge in the stomach was observed in females.

Recovery Observation
At 300 mg/kg, thickening of limiting ridge in the stomach remained in females, but a tendency toward recovery was observed.

Detailed Clinical Observation, Manipulative Test, Grip Strength and Motor Activity
There were no treatment-related effects on any item.
At 300 mg/kg, wheezing, which was thought to be caused by irritation of the test article, was observed in a few males, and wheezing, emaciation and hunched posture were observed in 1 female.



Effect levels

Dose descriptor:
NOAEL
Effect level:
12 mg/kg bw/day (nominal)
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Changes that were thought to be treatment-related were: mucosal hemorrhage and erosion/healed erosion in the glandular stomach, thickening of limiting ridge in the stomach and an increase in urinary protein in males and females; increases in

urinary urobilinogen, phosphate crystals in sediment and osmotic pressure of urine and a decrease in urine volume in males; and thickening of mucosa in the forestomach and an increase in urinary glucose in females at 300 mg/kg. At 60 mg/kg, increases in urinary

protein and phosphate crystals in sediment and a decrease in urine volume were observed in males and thickening of limiting ridge in the stomach was observed in females. At 12 mg/kg, no treatment-related effects were detected. Therefore, no-observed-effect level of FAM was assumed to be 12 mg/kg/day under the conditions of this study.

Applicant's summary and conclusion

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