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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:
other: OECD guideline 413 study conducted under GLP. The study was selected as a key study because the information provided for the hazard is sufficient to evaluate the need for classification and labelling and/or risk assessment.

Data source

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

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: 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 (e.g. ): ad libitum (overnight fast prior to necropsy)
- Water (e.g. ):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
- 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 for 13 weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 5000, 20000 and 50000 ppm
Basis:
analytical conc.
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: 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


OTHER:
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:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
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:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
No treatment related adverse effects observed

Effect levels

Dose descriptor:
NOAEC
Effect level:
50 000 ppm (analytical)
Sex:
male/female
Basis for effect level:
other: No adverse effects noted

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Exposure of rats to 5000, 15000 or 50000 ppm (23300, 69900, or 233000 mg/m3) test substance for 6hours 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 -level for male and female rats.