Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1992-01 - 1992-03
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented and performed under GLP compliance; although not performed according to a guideline, generally accepted scientific principles were met.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1996
Report Date:
1996

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Adult male Fischer 344/N rats received the test item 1,1,1-trichloro-2,2,2-trifluoroethane by gavage daily over a test period of 21 days. Subsequently, the liver and kidney of these rats were evaluated histopathologically. Urinalysis was also performed.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 1,1,1-Trichloro-2,2,2-trifluoroethane & 1,1,1TriC-2,2,2-TFE
- Physical state: liquid
- Color: colorless
- Analytical purity: 99%
- Impurities: 0.8% 1,1,2-trichloro-1,2,2-trifluoroethane (measured with gas chromatography)
- Lot/batch No.: 0730191-2
- Supplier: Columbia Organic Chemical Company, Inc., Camden SC
- Stability under test conditions: The test item showed losses in concentration when stored either at room temperature or at 5°C which wewre attributed to the volatility of the compound.
- Storage condition of test material: at room temperature in the dark

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Taconic Farms, Germantown NY
- Age at study initiation: 15 weeks
- Weight at study initiation: 286-288 g
- Housing: 5 per cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 15 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.6-23.9 °C
- Humidity (%): 35-65 %
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 1992-02-07 (first dosing) To: 1992-02-28

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Dose formulations were prepared by mixing the test item with corn oil and magnetical stirring. Due to concentration losses of the test item during storage, a second set of ftest item formulations was prepared for the last week of dosing.

VEHICLE
- Vehicle: Corn oil
- Amount of vehicle (if gavage): 5 mL/kg bw

Doses:
vehicle control
116.2 mg/kg bw/day (in report given as: 0.62 mmol/kg bw/day)
232.3 mg/kg bw/day (in report given as: 1.24 mmol/kg bw/day)
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
21 days on 7 d/week
Frequency of treatment:
once daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
116.2 mg/kg bw/day
Basis:
other: nominal dose
Remarks:
Doses / Concentrations:
232.3 mg/kg bw/day
Basis:
other: nominal dose
No. of animals per sex per dose:
5 male rats per dose group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on the results of a 2-year study performed with pentachloroethane (NTP Technical Report Series No. 232, NIH Publication No. 83-1788)
- Rationale for animal assignment: random distribution into groups of approximately equal initial mean body weight

The dose levels were set to 0.62 and 1.24 mmol/kg bw/day, which corresponds for 1,1,1-trichloro-2,2,2-trifluoroethane (187.376 g/mol) to 116.2 mg/kg bw/day and 232.3 mg/kg bw/day, respectively.

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

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY:No

URINALYSIS: Yes
- Time schedule for collection of urine: 4 days before end of the study
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in table 1 were examined.

NEUROBEHAVIOURAL EXAMINATION: No

OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table 2)
HISTOPATHOLOGY: Yes (see table 2)
Statistics:
Organ and body weight data: Dunnett-test
Urinalysis data: Dunn-test
Significance of dose-response trends: Jonckheere-test
Outlier test: according to Dixon and Massey

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
All rats administered 1,1,1-Tirchloro-2,2,2-trifluoroethane survived until the end of the study. No clinical signs of toxicity were observed.

BODY WEIGHT AND WEIGHT GAIN
The final mean body weights and mean body weight gains of dosed animals were not distinguishable to those of the control animals (Table 3).

URINALYSIS
There were no significant differences in urinalysis parameters between dosed and control males (Table 6).

ORGAN WEIGHTS
There were no significant differences in organ weights between dosed and control males (Table 5).

HISTOPATHOLOGY
No microscopic effects were present in either the kidney or the liver at either dose level (Table 4).

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 3: Survival and Body Weights of F344/N Rats in the 3-Week Gavage Study of 1,1,1-Trichloro-2,2,2-trifluoroethane

Dose [mg/kg bw/day]

Survival

Mean body weight [g]

Final weight relative to controls [%]

Initial

Final

Change

Vehicle control

5/5

291

323

33

 

116.2

5/5

288

328

40

102

232.3

5/5

286

320

34

99

 

Table 4: Kidney Effects in Male F344/N Rats in the 3-Week Gavage Study of 1,1,1-Trichloro-2,2,2-trifluoroethane

Dose [mg/kg bw/day]

Hyaline droplet nephropathy

Tubule regeneration

Granular casts

116.2

0

0/5

0/5

232.3

0

0/5

0/5

Table 5: Body and organ weights in Male F344/N Rats in the 3-Week Gavage Study of 1,1,1-Trichloro-2,2,2-trifluoroethane

Organ

Vehicle control

1,1,1-Trichloro-2,2,2-trifluoroethane [mg/kg bw/day]

116.25

232.50

Necropsy bw [g]

323±3

328±6

320±7

Right kidney

           absolute [g]

           relative [mg/g bw]

 

1.031±0.024

3.19±0.05

 

1.048±0.023

3.19±0.05

 

1.028±0.040

3.21±0.10

Liver

           absolute [g]

           relative [mg/g bw]

 

11.611±0.103

35.92±0.46

 

11.920±0.284

36.33±0.52

 

11.720±0.524

36.61±1.21

Right testis

           absolute [g]

           relative [mg/g bw]

 

1.435±0.038

4.44±0.11

 

1.472±0.025

4.49±0.10

 

1.354±0.080

4.24±0.27

 

Table 6: Urinalysis results of Male F344/N Rats in the 3-Week Gavage Study of 1,1,1-Trichloro-2,2,2-trifluoroethane

Endpoint

Vehicle control

1,1,1-Trichloro-2,2,2-trifluoroethane [mg/kg bw/day]

116.25

232.50

Creatinine [mg/dL]

97.46±9.43

72.58±8.61

85.14±16.11

Glucose [µg/mg creatinine]

160±6

205±11

161±12

Protein [µg/mg creatinine]

1.227±78

1.461±102

1.396±75

Aspartate aminotransferase [mU/mg creatinine]

8±1

16±4

13±1

g-Glutamyltransferase [mU/mg creatinine]

1.384±78

1.533±57

1.684±64

N-Acetyl-b-D-glucoseaminidase [mU/mg creatinine]

11±1

17±4

12±1

Volume [mL/16 h]

7.4±0.9

7.8±1.0

8.3±2.1

Specific gravity

1.023±0.002

1.020±0.002

1.021±0.003

Applicant's summary and conclusion

Conclusions:
No apparent toxicity was observed after 21 oral application of 1,1,1-trichloro-2,2,2-trifluoroethane to male F344/N rats.
Executive summary:
Repeated dose oral toxicity of 1,1,1-trichloro-2,2,2-trifluoroethane was assessed in a sub-acute 21 day study on male F344/N rats. The study was performed under GLP but no guideline was indicated.

Male rats were administered to the test item in corn oil (nominal concentrations 116.2 and 232.3 mg/kg bw/day) by gavage daily for 21 days. Clinical signs of toxicity and body weights were determined weekly. Cages were checked for dead animals twice a day. Necropsies were performed on all survivors. The right kidney, liver, and right testis were weighed. Organs and tissues were observed for gross lesions. Histopathologic examinations of the right kidney, liver (left lobe), and grossly visible lesions were performed. Urin was collected from all animals using metabolism cages and volume, specific gravity, creatinine, glucose, total protein, aspartate aminotransferase, g-glutamyl transpeptidase, and N-acetyl-D-glucosaminidase were determined.

No apparent signs of toxicity could be observed during or after 21 days of treatment. All animals survived until end of the study without showing clinical signs of toxicity. Body weights, weight gains, organ weights, and urinalysis parameters were similar to those of the controls. No microscopic effects were present in either kidney or liver.

Taken together, sub-acute oral administration of 1,1,1-trichloro-2,2,2-trifluoroethane in concentrations up to 232.3 mg/kg bw/day was not toxic to rats.