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Toxicological information

Repeated dose toxicity: inhalation

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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:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report date:
2007

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent

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 Deutschland
- Age at study initiation: 6 weeks
- Weight at study initiation: Mean weights 231 g (males) and 172 g (female)
- Fasting period before study: None
- Housing: Macrolon cages with wood shaving beding
- Diet: Ad libitum (overnight fast prior to necropsy)
- Water: Ad libitum
- Acclimation period: At least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 37-44
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: March 2006 To: June 2006

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
- Source and rate of air: At least 1 L/min
- Temperature, humidity in air chamber: 20-24C; 30-70%
- Air flow rate: At least 1 L/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 a day
Frequency of treatment:
5 days a week for 13 weeks
Doses / concentrationsopen allclose all
Dose / conc.:
5 000 ppm
Remarks:
Group 2: Low dose. Equivalent to 23300 mg/m3.
Dose / conc.:
15 000 ppm
Remarks:
Group 3: Mid dose. Equivalent to 69900 mg/m3.
Dose / conc.:
50 000 ppm
Remarks:
Group 4: High dose. Equivalent to 233000 mg/m3.
No. of animals per sex per dose:
10
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: 50000 ppm (5%) was chosen as the high dose group to prevent secondary effects due to oxygen deprivation that can occur at higher concentrations
- Post-exposure recovery period in satellite groups: None

Examinations

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

DETAILED CLINICAL OBSERVATIONS:
- Time schedule: daily

BODY WEIGHT:
- Time schedule for examinations: weekly

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

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

OPHTHALMOSCOPIC EXAMINATION: yes

HAEMATOLOGY:
- Time schedule for collection of blood: At scheduled necropsy
- Anaesthetic used for blood collection: Yes, Nembutal
- Animals fasted: Yes
- How many animals: All survivors
- Parameters listed in OECD guideline were examined.

CLINICAL CHEMISTRY:
- Time schedule for collection of blood: At scheduled necropsy
- Animals fasted: Yes
- How many animals: All survivors
- Parameters listed in OECD guideline were examined.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - those organs listed in the guideline plus nose (6-levels), larynx (3 levels), trachea (3 levels 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:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
not examined

Effect levels

Key result
Dose descriptor:
NOAEC
Effect level:
> 50 000 ppm (analytical)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
Equivalent to 233000 mg/m3.

Target system / organ toxicity

Key result
Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
Exposure of rats to 5000, 15000 or 50000 ppm (23300, 69900, or 233000 mg/m3) test substance for 6 hours a day, 5 days a week, for 64 or 65 exposure days over a 98 day period did not result in adverse effects in any of the exposure groups. In the present sub-chronic toxicity study, the high concentration level of 50000 ppm was therefore considered the No-Observed-Adverse-Effect-Concentration for male and female rats.