Registration Dossier

Administrative data

Description of key information

A key study is available for the acute oral, inhalation and dermal routes.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
There were temporary deviations from the minimum level of relative humidity. Evaluation: laboratory historical data do not indicate an effect of the deviations. he study integrity was not adversely affected by the deviations.
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no
Specific details on test material used for the study:
Clear colourless liquid, purity 96.5%.
Species:
rat
Strain:
Wistar
Remarks:
Wistar Crl / WI (outbred SPF quality)
Sex:
female
Details on test animals or test system and environmental conditions:
Nine femailes, age 9-10 weeks
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Single dosage on day 1
Doses:
2000 mg/kg (2.17 ml/kg) body weight
300 mg/kg (0.326 ml/kg) body weight
No. of animals per sex per dose:
3
Details on study design:
Post dose observation period: 14 days
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
300 - 2 000 mg/kg bw
Based on:
test mat.
Key result
Sex:
female
Dose descriptor:
LD50 cut-off
Effect level:
500 mg/kg bw
Based on:
test mat.
Mortality:
Number of deaths at each dose level:

2000 mg/kg 3/3
300 mg/kg 0/3
300 mg/kg 1/3
Clinical signs:
2000 mg/kg
Restless behaviour, lethargy, hunched posture, tremors (general), uncoordinated movements, laboured respiration, piloerection, ptosis and/or chromodacryorrhoea.

300 mg/kg
lethargy, restless behaviour, hunched posture, shallow respiration, quick breathing, piloerection, swelling of the snout and/or ptosis.
Other findings:
Necropsy findings:
Macroscopic post mortem examination of the animals treated at 2000 mg/kg revealed many dark red foci in the lungs and thymus and pale discolouration of the stomach.
No abnormalities were found in the animals dosed at 300 mg/kg.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The oral LD50 value of pentamethyl-trioxepane in Wistar rats was established to be within the range of 300-2000 mg/kg bw. According to the OECD guideline 423 the LD50 cut-off value was considered to be 500 mg/kg bw.
Executive summary:

The oral LD50 value of pentamethyl-trioxepane in Wistar rats was established to be within the range of 300-2000 mg/kg bw.

Data are conclusive and the substance is classified as Category 4 based on GHS criteria.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
300 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
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
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
fixed concentration procedure
Limit test:
yes
Specific details on test material used for the study:
Lot number 0905513112, Purity 98.4 %
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.
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.
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.
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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
5 112 mg/m³

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Five Wistar rats of each sex (females were nulliparous and non-pregnant).

Young adult animals (approx. 9 weeks old) were selected. Body weight variation did not exceed +/- 20% of the sex mean.

Conditions:
Animals were housed in a controlled environment, in which optimal conditions were considered to be approximately 15 air changes per hour, a temperature of 21.0 +/- 3.0 oC (actual range 19.6-22.7 oC), a relative humidity of 30-70% (actual range 27-64%) and 12 hours artificial fluorescent light and 12 hours darkness per day.

Accomodation:
Individually housed in labeled Macrolon cages (MIII type, height 15 cm.) containing sterilized sawdust as bedding material (Woody-Clean type 3/4; Technilab-BMI BV, Someren, The Netherlands) and paper as cage-enrichment (Enviro-dri, BMI, Helmond, The Netherlands). Acclimatization period was at least 5 days before start of treatment under laboratory conditions. During the acclimatization period the animals were group housed in Macrolon cages (MIV type).
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
Single application at 2000 mg/kg body weight
Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
five
Control animals:
no
Details on study design:
Observations:
Mortality/Viability: Twice daily
Body weights: Days 1 (pre-administration), 8 and 15
Clinical signs: At periodic intervals on the day of dosing (day 1) and once daily thereafter, until day 15. The time of onset, degree and duration were recorded and the symptoms graded according to fixed scales: Maximum grade 4 (grading slight (1) to very severe (4); Maximum grade 3 (grading slight (1) to severe (3); Maximum grade 1 (presence is scored (1).
Necropsy: At the end of the observation period, all animals were sacrificed by oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
none
Clinical signs:
Chromodacryorrhoea, hunched posture and/or ptosis were noted in some animals on days 1 and/or 2. In one femaile, scabs were noted in the nect from day 9 onwards.
Body weight:
The changes noted in body weight gain in males and females were within the range expected fro rats used in this type of study and were therefore considered not indicative of toxicity.
Other findings:
In one animal the left testis was reduced in size
Interpretation of results:
GHS criteria not met
Conclusions:
The dermal LD50 value of Pentamethyl-trioxepane in Wistar rats was established to exceed 2000 mg/kg body weight
Executive summary:

The dermal LD50 value of Pentamethyl-trioxepane in Wistar rats was established to exceed 2000 mg/kg body weight.

Data are conclusive but not sufficient for classification.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

Justification for classification or non-classification

Data are conclusive for the acute toxicity by inhalation and dermal routes and are not sufficient for classification. The oral acute toxicity data are conclusive and sufficient for classification: Per GHS criteria, classified as Cat 4.