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Diss Factsheets

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
07. January 2019 - 13. March 2019
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019
Report date:
2019

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Qualifier:
according to guideline
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
GLP compliance:
yes (incl. QA statement)
Test type:
traditional method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Dimethyl 2,2'-azobis(2-methylpropionate)
EC Number:
219-976-6
EC Name:
Dimethyl 2,2'-azobis(2-methylpropionate)
Cas Number:
2589-57-3
Molecular formula:
C10H18N2O4
IUPAC Name:
dimethyl 2,2'-azobis(2-methylpropionate)
impurity 1
Reference substance name:
unknown
Molecular formula:
unknown
IUPAC Name:
unknown
Test material form:
solid: crystalline
Details on test material:
Batch No: HG6021
date of production: 09/2017

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories,
Research Models and Services, Germany GmbH,
Sandhofer Weg 7,
97633 Sulzfeld
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: (male animals approx. 9 - 10 weeks, female animals approx.
11 – 12 weeks)
- Weight at study initiation: Animals of comparable weight (± 20% of the mean weight 186.4 - 314.7 g)
- Fasting period before study:
- Housing: Single housing or up to 5 animals (caged in groups)
- Diet (e.g. ad libitum): Mouse and rat maintenance diet, GLP, 12 mm pellets, Granovit
AG, Kaiseraugst, Switzerland
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: Acclimatization for at least 5 days before exposure

ENVIRONMENTAL CONDITIONS
Room temperature / relative humidity:
The animals were housed in air-conditioned rooms. Central airconditioning
guaranteed a range of 20 – 24°C for temperature
and of 45 – 65 % for relative humidity.There were no deviations
from these ranges, which influenced the results of the study.
There were15 air changes per hour.
Day / night rhythm: 12 h / 12 h (6.00 a.m. – 6.00 p.m. / 6.00 p.m. – 6.00 a.m.)


IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
clean air
Mass median aerodynamic diameter (MMAD):
>= 0.3 - <= 1.6 µm
Geometric standard deviation (GSD):
>= 2.7 - <= 4
Details on inhalation exposure:
Test-substance preparation: Test-substance preparations:
Test group 1:
Test substance (30 g) was mixed with Ethanol (188 g). In
addition, ultrapure water (282 g) was added to the mixture.
Test group 2:
Test-substance (56.0 g was mixed with Ethanol (146.8 g). In
addition, ultrapure water (206.4 g) was added to the mixture.
Test group 3:
Test-substance (250.0 g) was mixed with Ethanol (483.0 g). In
addition, ultrapure water (267.0 g) was added to the mixture.
The test-substance preparations were produced shortly before
exposure. After stirring with a magnetic stirrer, the test
substance is soluble in ethanol and ultrapure water and the testsubstance
preparations were solutions.
Equipment: - Two-component atomizer Mod. 970 (stainless steel, Schlick)
- Magnetic stirrer
- Balance (Mettler)
- Piston metering pump KP 2000 (Desaga/Sarstedt)
Generation technique: Liquid aerosols were generated.
For each test group the aerosols were produced by continuously
pumping amounts of the test-substance solution to a
two-component atomizer. Using compressed air, the aerosol
was produced with the atomizer inside the exposure system.
Nose-only inhalation system INA 20 (glass-steel construction, BASF SE, volume V 55 L):
the animals were restrained in glass tubes and their snouts projected into the inhalation system.
The homogenous distribution of test substance atmosphere/s in this inhalation system has
been verified with model aerosols.
Conditioned air:
The central air conditioning system provides cold air of about 15°C. This cold air passes
through an activated charcoal filter, is adjusted to room temperature of 20 to 24°C and passes
through a second particle filter (H13 (HEPA) Camfil Farr, Germany). The generated
conditioned air was used to generate inhalation atmospheres.
Compressed air:
Compressed air was produced by an oil-free compressor (HT 6, Josef Mehrer GmbH & Co KG,
Germany). For this purpose, air is filtered by an inlet air strainer and introduced into the
compressor. After passing through a second ultra-filter (SMF 5/3, 108 mm, Donalson), the
compressed air (15 bar) is stored in a storage of 1500 or 5000 L. The compressed air is
conducted to the laboratories via pipes, where the pressure is reduced to 6 bar. In the
laboratory, the compressed air can be taken as required.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
0.560, 1.935 and 3.994 mg/L (analytical concentration)
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
A check for any dead or moribund animal was made twice each
workday and once on Saturdays, Sundays and on public
holidays.
Individual body weights once during the acclimatization period,
shortly before exposure (day 0) and at least on days 1, 3 and 7,
and before the sacrifice of the animals at the end of the
observation period. Additionally, body weight was measured in
animals that died or were sacrificed in a moribund state from
study day 1 onwards.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other:
Clinical observations were recorded for each animal before
exposure, separately several times during exposure (usually
hourly) and after exposure as well as at least once during the
pre-exposure day and daily during the post-exposure
observation period.
At the end of the observation period the surviving animals were
sacrificed with CO2-inhalation in a chamber with increasing
concentration over time and were subjected to
gross-pathological examination as well as the animal which
died or were sacrificed in a moribund state before. Each
moribund animal, which most probably would have died on
account of the toxic effects of the test substance was sacrificed
during the observation period according to the German Animal
Protection Law (BGBL I, 22 Aug 1986).
Statistics:
Statistical analyses were performed using the SAS [2] procedure Proc Probit.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
2.034 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
No mortality was observed in male and female animals during the study period of 14 days.
Test group 2 (1.935 mg/L):
One of five male animals and two of five females died on study day 1, 2 or 3.
Test group 3 (3.994 mg/L):
All the five male animals and all of the five females died or were sacrificed in a moribund state
on study day 0 after exposure.
Clinical signs:
other: The following clinical signs and findings were observed during (up to 4 hours) and after exposure (> 4 hours). Test group 1 (0.560 mg/L): No abnormalities were detected in the animals of the test groups 1 during the study period. Test group 2 (1.935 mg/L)
Body weight:
Test group 1 (0.560 mg/L):
The mean body weights of the animals decreased on the first post-exposure observation day
but increased thereafter. This is a typical finding for this test design.
Test group 2 (1.935 mg/L):
The mean body weights of the surviving animals decreased on the first post-exposure
observation day but increased thereafter. This is a typical finding for this test design.
Test group 3 (3.994 mg/L):
No body weight data were available because all animals died or were sacrificed in a moribund
state on study day 0 after exposure.
Page
Gross pathology:

Findings test group 2 test group 3
Number of animals 1 male + 2 females 5 males + 5 females
Organs without particular findings 4 males + 4 females
Lung (Pulmo sinister and right cardiacus
lobe: few red foci
1 female -
Glandular stomach:
dark-red focus
1 female -
Glandular stomach:
few black foci
1 male -
Liver:
prominent acinar pattern
1 male -
Lung:
Edema
- 1 male
Small intestine:
Dilation with gaseous content
- 1 female
No gross pathological abnormalities were noted during the necropsy in all animals of test
group 1 and in the surviving four males and three female animals of the group 2 at the
termination of the post-exposure period.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Under the study conditions, the LC50 value was 2.034 mg/L (calculated based on analytical
concentration of the formulation) in male and female Wistar rats after a 4-hour inhalation
exposure to the liquid aerosol of Dimethyl 2,2'-azobis(2-methylpropionate).
Executive summary:

To determine the acute inhalation toxicity (single 4-hour exposure, nose only) of Dimethyl 2,2'-azobis(2-methylpropionate) as a liquid aerosol, a study was performed in male and female

Wistar rats according to OECD-Guideline method 403 as well as EC. For technical reasons the test substance was sprayed as solution in ethanol and ultrapure water.

The actual measured concentrations were: 0.560, 1.935 and 3.994 mg/L (analytical concentration).

Cascade impactor measurements resulted in particle size distributions with mass median aerodynamic diameters (MMADs) between 0.3 and 1.6 μm, which are well within the respirable

range.

No mortality was occurred at the tested concentration of 0.560 mg/L. One of the five males and two of five females died at 1.935 mg/L on study day 1, 2 or 3. At 3.994 mg/L all of the male and female animals died or were sacrificed in a moribund state. Mortality was observed after exposure on study day 0.

No abnormalities were detected in the animals exposed to 0.560 mg/L during the study period. The mean body weights of the animals decreased on the first post-exposure observation day

but increased thereafter. No gross pathological abnormalities were noted in all five males and all five females at the termination of the post-exposure period.

Clinical signs of toxicity in animals exposed to 1.935 mg/L comprised abdominal and intermittent respiration, nasal red discharge and red encrusted nose, salivation indicating a

local irritation effect. Moreover, reduced attention, hyperesthesia, hyperexcitability, absence of feces, high-stepping gait, unsteady gait and piloerection were also observed. Findings were

observed from hour 4 of exposure through study day 7. No clinical signs and findings were observed from study day 8 onwards. The mean body weights of the surviving animals

decreased on the first post-exposure observation day but increased thereafter. Gross necropsy of the male animal and the two female animals that died showed few red foci of the lung, darkred

focus in the glandular stomach or few black foci or a prominent acinar pattern of the liver. The remaining four males and three female animals showed no gross pathological abnormalities during the necropsy at the termination of the post-exposure observation period.

Clinical signs of toxicity in animals exposed to 3.994 mg/L comprised abdominal respiration, gasping respiration, intermittent and labored respiration indicating a local irritation effect.

Moreover, abdominal and lateral position, extension convulsions, unconsciousness and substance-contaminated fur also observed. Findings were observed from hour 1 of exposure

through after exposure. No body weight data were available because all animals died or were sacrificed in a moribund state. During necropsy of the five male animals and five female

animals that was found dead or were sacrificed in a moribund state on study day 0, edema of the lung was noted in one male and dilation with a gaseous content of the small intestine in

one female.