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Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
February 18, 2000 - November 12, 2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
The informtion for this endpoint study record was obtained from an experimental study. The OECD GLP criteria were met and the methods applied are fully compliant with OECD TG 407

Data source

Reference
Title:
Unnamed
Year:
2000
Report date:
2001

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
only 6 animals per dose group, 4 dose groups, dose spacing increased to factor of 5, recovery in three groups
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
4-trans-Propyl-4-trans-(3,4,5-trifluorphenyl)-[1,1-bicyclohexyl]
EC Number:
603-522-2
Cas Number:
131819-23-3
Molecular formula:
C21H29F3
IUPAC Name:
4-trans-Propyl-4-trans-(3,4,5-trifluorphenyl)-[1,1-bicyclohexyl]
Test material form:
solid
Specific details on test material used for the study:
lot No. E998833

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 5 weeks
- Weight at study initiation: 141- 161 g (m), 114-141 g (f)
- Fasting period before study: no
- Housing: grouped
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

DETAILS OF FOOD AND WATER QUALITY:
Pellet diet for experimental animals (MF, Oriental Yeast Co., Ltd.) and

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20" to 24" C
- Humidity (%): 40% to 70%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12 h

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
Tue test substance was suspended in a 0.5% CMC-Na aqueous solution mixed with 0.1 % Tween 80 (Tween 80: Tokyo Kasei Kogyo Co., Ltd., lot No. GEOl; CMC-Na: Iwai Chemicals Company, lot No. 041210). The dosing solutions were prepared once a week, and
were stored in a dark refrigerated place. They were used within 8 days. The dosing solutions were stirred just before administration.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The homogeneity and stability of the test substance in the dosing solution which is stored in a dark refrigerated place for 8 days were confirmed at the doses of 0.4 and 100 mg/mL by the HPLC method before the first administration. The dosing solutions for each dose group prepared at the first time were analyzed by the HPLC method and confirmed that the concentrations of the test substance were within ± 10% for each indicated concentration.
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
8 mg/kg bw/day (actual dose received)
Dose / conc.:
40 mg/kg bw/day (actual dose received)
Dose / conc.:
200 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
Group name (mg/mL) Main Male Main Female Recov. Male Recov. Female
Control 0 6 6 6 6
8 mg/kg 0.8 6 6
40 mg/kg 4.0 6 6
200 mg/kg 20 6 6 6 6
1000 mg/kg 100 6 6 6 6
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on DRF study results
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: recovery animals
- Post-exposure recovery period in satellite groups: 14 days
- Section schedule rationale (if not random): random

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All rats were observed twice a day (before and after administration) during the treatment
period and once a day on every other day in the morning.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / Not specified
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: Yes / No / Not specified
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Days 29 and 43
- Anaesthetic used for blood collection: Yes (Ravonal)
- Animals fasted: No
- How many animals:
- Parameters checked in table [No.?] were examined.

CLINICAL CHEMISTRY: Yes / No / Not specified
- Time schedule for collection of blood:
- Animals fasted: Yes / No / Not specified
- How many animals: 6


URINALYSIS: Yes
- Time schedule for collection of urine: day 23
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: No

NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:

IMMUNOLOGY: No
- Time schedule for examinations:
- How many animals:
- Dose groups that were examined:
- Parameters checked in table [No.?] were examined.

OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Tue following organs of all rats were weighed with an electronic balance (AEG-120,
Shimadzu Corp.). Tue relative organ weights (organ to body weight ratio) were calculated
from the body weight on the day of necropsy.
Brain, liver, kidneys, adrenals, thymus, spleen, testes, and ovaries.


HISTOPATHOLOGY: Yes
Tue following organs and tissues were removed from all rats and fixed in a 10% neutral
phosphate-buffered formalin, except for the eye and Harderian gland which were fixed in
Davidson's solution, and for testis and epididymis which were fixed in Bouin's fluid.
Brain, pituitary, eye and Harderian gland, thymus, lung, stomach, thyroid and parathyroid,
heart, liver, spieen, kidney, adrenal, urinary bladder, testis, epididymis, ovary, and hone
marrow (femur, unilateral).
Histopathological examination was perf orrned on the following organs and tissues of the
control and 1000 mg/kg groups at the end of the treatment period, along with all gross lesions
found in any group.
Histological specimens were stained with H.E. stain in accordance with
routine methods and examined. Additionally, the liver, adrenal, and Harderian gland of all
males and females of other doses at the end of the treatment period and all of the groups at the
end of the the recovery period were also examined histologically, since the change considered
to be caused by the administration of the test substance were found in these organs.
Further, since focal necrosis in the bone marrow was noted in one male of the 1000 mg/kg group,
to determine the incidence of this change, the bone marrow was also
examined in the rnales of other dose groups at the end of the treatment period.
Heart, liver, spieen, kidney, adrenal, Harderian gland, bone marrow.
Statistics:
Standard statistical methods have been applied for data processing.

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):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
At the end of the treatment period, increased reticulocyte count was noted in the males of the 200 and 1000 mg/kg groups and shortened prothrombin time in the females of the 1000 mg/kg group. These changes were not observed at the end of the recovery period.
In addition, shortened prothrombin time was noted at the end of the recovery period in the females of the 200 mg/kg group. However, this change was slight and was not noted at the end of the recovery period in the 1000 mg/kg group, so it was considered unrelated to test substance adrninistration.
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
At the end of the treatment tperiod, the absolute and relative weights of the liver were increased in the males of the 200 and 1000 mg/kg groups, the absolute weight of the adrenals was increased in the females of the 40 and 1000 mg/kg groups, and the relative weight of the adrenals was increased in the females of the 200 and 1000 mglkg groups. These changes were not observed at the end of the recovery period.
In addition, at the end of the treatment period, the absolute weight of the kidneys was increased in the males of the 200 mglkg group and at the end of the recovery period, the absolute weight of the spleen and the relative weight of the liver were decreased in the males
of the 200 mg/kg group. However, these changes were slight and any of them was not noted in the 1000 mg/kg group, so it was considered unrelated to test substance administration.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
At the end of the treatment period, enlargement of the liver was noted in the animals of both sexes of the 200 and 1000 mg/kg groups, enlargement of the adrenal in the females of the 1000 mg/kg group, and a brown change in the Harderian gland in the females of the 40 mg/kg bw/d group and the animals of both sexes of the 200 and 1000 mg/kg bw groups. At the end of the recovery period, only the brown change in the Harderian gland was still noted in the females of the 200 mg/kg bw/d group and the animals ofboth sexes of the 1000 mg/kg bw/dgroup.
In addition, in the test substance-treated groups, brown patch in the lung was noted at the end of the treatment period. However, since the incidence of this change showed no constant tendency, it was considered unrelated to test substance administration.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Liver Hypertrophy, hepatocyte, centrilobular
Adrenal Increase in lipid droplet, fascicular zone
Harderian gland Hypersecretion

Effect levels

open allclose all
Key result
Dose descriptor:
NOEL
Effect level:
8 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Key result
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic

Target system / organ toxicity

Key result
Critical effects observed:
no

Any other information on results incl. tables

Total incidences of necropsy findings


Period
End of treatment
End of recovery
Organ
Sex
Male
Female
Male
Female

Dose [mg/kg]
0
8
40
200
1000
0
8
40
200
1000
0
200
1000
0
200
1000

Number of animals
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
Liver
centrilobular hypertrophy grade 1 0
0
4
4
5
0
0
0
2
5
0
0
1
0
0
1
Adrenal increase lipid droplet, fascilar zone grade 1
0
0
0
0
4
0
0
0
1
1
0
0
0
0
0
0
Adrenal
increase lipid droplet, fascilar zone grade 2
0
0
0
0
0
0
0
0
0
3
0
0
0
0
0
0
Harderian gland
hypersecretion
0
0
0
1
4
0
0
2
4
4
0
0
1
0
3
4


Applicant's summary and conclusion

Conclusions:
A NOEL (no effect level) of 8 mg/kg bw/ for both sexes and the NOAEL (no observed adverse effect level) of 200 mg/kg bw/day are considered justified.