2,2,3,3,3-pentafluoropropanol

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

02 November 1989-14 December 1989

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

Version / remarks:

Adopted 12 May 1981.

Deviations:

yes

Remarks:

Results with tables are not available

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: Circular on Test Methods of New Chemical Substances (Japan), repeated dose toxicity for 28 days in mammals

Version / remarks:

Adopted 5 december 1986

Deviations:

no

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2,2,3,3,3-pentafluoropropanol

EC Number:

207-012-7

EC Name:

2,2,3,3,3-pentafluoropropanol

Cas Number:

422-05-9

Molecular formula:

C3H3F5O

IUPAC Name:

2,2,3,3,3-Pentafluoropropan-1-ol

Test material form:

liquid

Test animals

Species:

rat

Strain:

other: CD (SD)

Remarks:

Specific Pathogen Free

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Japanese Charles River, Atsugi, Kanagawa Prefecture, Japan
- Females: yes
- Age at study initiation: 6 weeks
- Weight at study initiation: 65 - 85 g (males) and 60 - 80 g (females)
- Fasting period before study: no fasting
- Housing: stainless steel cages with mesh flooring
- Diet: CRF-1 pelleted, not further specified, ad libitum
- Water: municipal tap water, ad libitum
- Acclimation period: at least fourteen days, last seven to inhalation chamber

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2
- Humidity (%): 45 - 65
- Air changes (per hr): 15 - 17
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 02 November 1989 To: 14 December 1989

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

clean air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: stainless steel exposure chamber, not further specified
- Exposure chamber volume: 1.06 m³
- Source and rate of air: indoor air
- Method of conditioning air: filtered
- System of generating particulates/aerosols: test material was evaporated by bubbling in a heated atmosphere
- Treatment of exhaust air: charcoal filter
- Temperature, humidity, pressure in air chamber: 22-25°C, 30-70%, 0-15 mm Aq

TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatography every 15 minutes
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Remarks:

GC

Details on analytical verification of doses or concentrations:

Test atmosphere concentrations were verified by gas chromatography. The analytical data indicated that the variance between nominal and actual concentrations were acceptable.

Duration of treatment / exposure:

28 days

Frequency of treatment:

6 h/day, 5 days/week, for 4 weeks

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

40 ppm (nominal)

Remarks:

40.0 ppm analytical result (0.245 mg/L vapour converted from ppm)

Doses / concentrations 2

Dose / conc.:

100 ppm (nominal)

Remarks:

100.1 ppm analytical result (0.614 mg/L vapour converted from ppm)

Doses / concentrations 3

Dose / conc.:

260 ppm (nominal)

Remarks:

259.2 ppm analytical result (1.591 mg/L vapour converted from ppm)

Doses / concentrations 4

Dose / conc.:

640 ppm (nominal)

Remarks:

639.8 ppm analytical result (3.926 mg/L vapour converted from ppm)

Doses / concentrations 5

Dose / conc.:

1 600 ppm (nominal)

Remarks:

1597.2 ppm analytical result (9.801 mg/L vapour converted from ppm)

No. of animals per sex per dose:

5 males and females at each concentration in the main study
5 males and females (control, 640 and 1600 ppm) in the 14-day recovery group

Control animals:

yes, concurrent vehicle

Details on study design:

- Post-exposure recovery period in satellite groups: 14-day recovery period for control, 640, and 1600 ppm male and female animals

Positive control:

none

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: Day 0 (before administration), 2, 5

FOOD CONSUMPTION: Yes

FOOD EFFICIENCY: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at main dosing study terminations and recovery group terminations
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: 5 males and females at each exposure concentration (main dosing study), and the remainder at the end of the recovery period

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at main dosing study terminations and recovery group terminations
- Animals fasted: Not specified
- How many animals: 5 males and females at each exposure concentration (main dosing study), and the remainder at the end of the recovery period

URINALYSIS: Yes
- Time schedule for collection of urine: final week of each of the main dosing and recovery periods
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Not specified

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Statistics:

Means ± SD for most parameters

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Decline in self-mobility, prone posture, hunched position, ataxic gait, lacrimation, abnormal breathing (decreased respiration), and decreased body temperature were frequently observed following dosing. Additionally, occasional over-turning, loss of aural, tactile, and righting reflex, abnormal breathing (irregular breathing), and soiling were noted. For the clinical signs noted during the main dosing study, symptoms generally recovered by the next morning, and frequency of cases declined gradually during the main dosing period. Therefore fewer cases were found in the final week of the dosing period, and no symptoms were observed during the recovery period.

For males and females in dose groups 640 ppm and 1600 ppm, piloerection and corneal opacity were observed during the main dosing study. Piloerection mostly reversed during the recovery period, but corneal opacity did not resolve and was found at the end of the recovery period.

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

For the males in dose group 5 (1600 ppm): reduction in body weight gain during the main and recovery periods was observed

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

For the males in dose group 5 (1600 ppm): slight reduction in food consumption during the main study period.

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

End of the main study period: slight tendency of anemia in males in dose group 5 (1600 ppm). For females in dose groups 4 (640 ppm) and 5 (1600 ppm): increased prothrombin time was observed.Tt the end of the recovery period the males showed no longer anemia, but increased prothrombin time in females in dose group 5 persisted, however it was mild.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

End of the main study period: reduction of total cholesterol and phosphatide for males in all dose groups, reduction of total protein in dose group 5 (1600 ppm), and increase in A/G ratios in dose groups 4 (640 ppm) and 5 (1600 ppm).
End of the recovery period: increased total cholesterol and phosphatide for dose group 5 (1600 ppm) males, which was the opposite of these effects seen at the end of the main study period.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

Final week of the main study: reduction in urine cholesterol for dose group 5 (1600 ppm) males. Additionally at this time point, urine volume was increased for both males and females in dose group 5 (1600 ppm).

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

At the end of the main study period: increase in actual weight and relative weight of liver for the males in dose groups 4 (640 ppm) and 5 (1600 ppm), increase in the relative weight of liver for the males in dose group 3 (260 ppm), and increase in actual weight and relative weight of liver for the females in dose group 5 (1600 ppm). Additionally, thymus and spleen weights were reduced for the males in dose group 5 (1600 ppm).

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

At the end of the main dosing study period, corneal opacity in males and females in dose group 5 (1600 ppm). This observation continued to be noted through the end of the recovery period in males and females in dose groups 5 (1600 ppm), and in males in dose group 4 (640 ppm).

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

At the end of the main study period, eosinophilic fine granular degeneration of liver cells was observed for males in dose groups 3 (260 ppm), 4 (640 ppm), and 5 (1600 ppm), and in females in dose group 5 (1600 ppm). Additionally, a reduction in liver fat was observed in the males and females in dose group 5 (1600 ppm). Degeneration of cornea and mineral deposition were observed in males and females in dose group 5 (1600 ppm), and females in dose group 4 (640 ppm). None of the liver changes observed at the end of the main dosing period were observed at the end of the recovery period. However, mineral deposition at the cornea was observed in all males and females in dose group 5 (1600 ppm) at the end of the recovery period. Additionally, degeneration of the cornea in males, and blood vessel formation and bleeding of the cornea in females, were noted dose group 5 (1600 ppm).

Histopathological findings: neoplastic:

no effects observed

Details on results:

Although the clinical biochemistry tests showed a reduction in total cholesterol and phosphatide for males in all dose groups, it was not considered a trending harmful effect clearly indicating a dose response as it did not correspond to any specific dose levels. However, because of the weight increase of liver (weight ratio only in dose group 3; 260 ppm) and the histopathologic change (eosinophilic fine granular degeneration of liver cells) that was observed in males in the 3 higher dose groups (above 100 ppm), the exposure concentration for dose group 3, i.e., 260 ppm, was considered as a toxic effect level. The subacute exposure level of 100 ppm was considered as the NOAEC under the conditions of this study.

Effect levels

1

Key result

Dose descriptor:

LOAEC

Effect level:

ca. 1.591 mg/L air (analytical)

Based on:

test mat.

Remarks:

converted from 260.0 ppm

Sex:

male/female

Basis for effect level:

clinical biochemistry

clinical signs

haematology

histopathology: non-neoplastic

2

Key result

Dose descriptor:

NOAEC

Effect level:

ca. 0.614 mg/L air (analytical)

Based on:

test mat.

Remarks:

converted from 100.0 ppm

Sex:

male/female

Basis for effect level:

clinical biochemistry

clinical signs

histopathology: non-neoplastic

Target system / organ toxicity

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

1.591 mg/L air (analytical)

System:

hepatobiliary

Organ:

liver

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Applicant's summary and conclusion

Conclusions:

Under the conditions of this study, the NOAEC level was found to be 100.0 ppm, and the LOAEC was found to be 260.0 ppm.
However, to establish the exposure scenarios based on a vapour exposure as described in the study, the units of ppm must be converted to units of mg/L. To do this, use the following formula: (ppm) x (MW of 150.05)/ 24.4529 which yields an exposure in mg/ m³, which can then be converted to units of mg/L by dividing (m³) by 1000.
NOEC male/ female for vapour: 0.61 mg/L
LOAEC male/female for vapour: 1.60 mg/L