Registration Dossier

Toxicological information

Repeated dose toxicity: inhalation

Currently viewing:

Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: OECD guideline study conducted under GLP

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008
Report Date:
2008

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland
- Age at study initiation: 7-8 weeks
- Weight at study initiation: mean weights 252 g (males) and 176 g (female)
- Fasting period before study: none
- Housing: macrolon cages with wood shaving beding
- Diet (e.g. ): ad libitum (overnight fast prior to necropsy)
- Water (e.g. ):ad libitum
- Acclimation period: at least 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 36-46 (one day humidity in high dose group was > 70% for less than 5 minutes- quickly fixed)
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: March 2007 To: June 2007

Administration / exposure

Route of administration:
inhalation: gas
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:cylindrical PVC column with a volume of ~ 70 liters surrounded by a transparent hook. The test atmosphere was introduced at the bottom and exhausted at the top
- Method of holding animals in test chamber:
- Source and rate of air: at least 1 lter/min
- Temperature, humidity in air chamber: 20-24C; 30-70%humidity
- Air flow rate: at least 1 liter/min


TEST ATMOSPHERE
- Brief description of analytical method used: total carbon analysis
- Samples taken from breathing zone: yes


Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
total carbon analysis
Duration of treatment / exposure:
6 hours day
Frequency of treatment:
5 days a week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 1500, 5000 and 15000 ppm
Basis:
analytical conc.
No. of animals per sex per dose:
10
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: 15000 ppm (1.5%) was chosen due to the effects observed in the range finding study
- Post-exposure recovery period in satellite groups: none

Examinations

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

DETAILED CLINICAL OBSERVATIONS: Yes (daily)

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for per group determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

OPHTHALMOSCOPIC EXAMINATION: yes

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at scheduled necropsy
- Anaesthetic used for blood collection: Yes (identity) -Nembutal
- Animals fasted: Yes
- How many animals: all survivors
- Parameters listed in OECD guideline were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at scheduled necropsy
- Animals fasted: Yes
- How many animals: all survivors
- Parameters listed in OECD guideline were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: no
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - those organs listed in the guideline plus nose (6-levels), larynx (3 levels), trachea (3 levles including bifurcation), and each lung lobe at 1 level.
Statistics:
Data were evaluated by the appropriate statistical test (one-way analysis of variance followed by Dunnett's multiple comparison test, one-way analyis of variance (ANOVA) followed by Dunn't multiole comparison testes, Krisckal-Wallis nonparametric Anova followed by Mann-Whitney U-tests, Fischers exact probability test.

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:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional 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:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
HAEMATOLOGY - concentration of the monocytes and thrombocytes were increased in male animals of the high concentration group.


CLINICAL CHEMISTRY - increased AST in high dose males, increased urea in high dose females


HISTOPATHOLOGY: NON-NEOPLASTIC-multifocal mononuclear cell infiltrates, often accompanied by myocardial degeneration (increased eosinophilia and pyknotic nuclei). A silver stain for reticulum did not provide evidence for fibrosis in high dose male and female

Effect levels

Dose descriptor:
NOEC
Effect level:
5 000 ppm (analytical)
Sex:
male/female
Basis for effect level:
other: multifocal mononuclear cell infiltrates in the heart of the 15000ppm males and females.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Overall, exposure of rats to 1500, 5000 or 15,000 ppm HFO-1234ze for 6 h/day, 5 days/week for 63 or 64 exposure days over a 91-92 day period did result in slight adverse effects in animals of the high concentration group only. In the present subchronic inhalation toxicity study, the mid concentration level of 5000 ppm was therefore considered to be a No-Observed-Adverse-Effect-Level (NOAEL) for male and female rats.
Executive summary:

Overall, exposure of rats to 1500, 5000 or 15,000 ppm HFO-1234ze for 6 h/day, 5 days/week for 63 or 64 exposure days over a 91-92 day period did result in slight adverse effects in animals of the high concentration group only. In the present subchronic inhalation toxicity study, the mid concentration level of 5000 ppm was therefore considered to be a No-Observed-Adverse-Effect-Level (NOAEL) for male and female rats.