Registration Dossier

Administrative data

Endpoint:
acute 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:
2010
Report date:
2010

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
fixed concentration procedure
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Specific details on test material used for the study:
Lot number 0905513112, Purity 98.4 %

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Healthy young adult Sprague-Dawley rats were received from Vital River Laboratories. At experiment initiation, the animals were 8-12 weeks of age. The animals were acclimatized to the animal room conditions for at least 5 days. At the study start the variation of individual weights did not exceed 10% of the mean for each sex. Animals were identified by individual color-marking and cage cards. Cage cards displaying at least the study number, animal number and sex were affixed to each cage. Housing was in plastic cages of appropriate sizes with stainless steel wire cover and chopped wood bedding. All animal rooms were maintained under a 12h light-dark cycle with temperature ranging from 23-25 oC, and relative humidity of between 30-70 % throughout this study. During the acclimatization and study periods the animals were housed in Animal Center of New Drug Safety Evaluation Center in Chinese Academy of Medical Sciences & Peking Union Medical College. Standard pelleted rat feed (Animal Center Military Medical Science Academy) was provided ad libitum to the animals throughout the study. Municipal tap water treated by reverse osmosis was available ad libitum throughout the study.

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
not specified
Remarks:
noted as aerosolized without the use of any additional vehicle
Mass median aerodynamic diameter (MMAD):
1.77 µm
Geometric standard deviation (GSD):
1.77
Remark on MMAD/GSD:
MMAD +/- 0.02 um
GSD +/- 0.1
Details on inhalation exposure:
Aerosol was generated by a aerosol generator (TSI, 8108, USA). The samples for the analysis of aerodynamic particle-size distribution were taken in the vicinity of the breathing zone. The particle-size distribution was analyzed using a aerodynamic particle-sizer Spectrometer (TSI, 3321, USA).
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
target 5000 mg/L
actual 5112+/-117
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Observations:
Cage-side observations included changes in the skin and fur, eyes and mucous membranes, and also respiratory, circulatory, autonomic and central nervous systems, and somatomotor activity and behavior patterns. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhea, lethargy, somnolence and prostration.

Body weight:
Body weight were measured once during the acclimatization period, on the day of exposure prior to exposure (day 0), and at least on days 1, 3 and 7, and weekly thereafter.

Gross Necropsy:
All rats, irrespective of the day of death, were given a gross pathological examination. Consideration was given to performing a gross necropsy on animals as indicated by the nature of toxic effects, with particular reference to changes related to the respiratory tract. All gross pathological changes were recorded and evaluated.

Temp. 21.7 oC; humidity 47 %, airflow 5 L/min
Statistics:
Data from the limit test were analyzed and an LC50 value estimated as follows:
< 50% Mortality: LC50 was estimated as greater than the administered dose.
= 50% Mortality: LC50 was estimated as equal to the administered dose.
> 50% Mortality: LC50 was estimated as less than the administered dose.

Body weight means and standard deviations were calculated separately for males and females for each limit level administered.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
>= 5 112 mg/m³ air (analytical)
Based on:
test mat.
95% CL:
117
Exp. duration:
4 h
Mortality:
none
Clinical signs:
other: The most notable clinical abnormalities observed during the exposure included rough coat, nasal secretions, salivation, tremors. These clinical abnormalities were observed on the day 0 of exposure, but then disappeared after 24h
Body weight:
A slight body weight loss was noted for the male rats at day 1, and for female rats at day 1 and 3. Normal body weight gain resumed for all other animals after that.
Gross pathology:
No significant gross internal findings were observed at necropsy on study day 14.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The acute inhalation LC50 of 3,3,5,7,7-pentamethyl-1,2,4-trioxepane was estimated to be greater than 5112 mg/m3 in the rat.
Executive summary:

The acute inhalation LC50 of 3,3,5,7,7-pentamethyl-1,2,4-trioxepane was estimated to be greater than 5112 mg/m3 in the rat. Data are consclusive but not sufficient for classification.