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Diss Factsheets

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2017-2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report date:
2018

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
Traditional Protocol adopted September 7, 2009
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Version / remarks:
Regulation (EU) No. 260/2014 of January 24, 2014 amending Regulation (EC) No. 440/2008
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes

Test material

1
Chemical structure
Reference substance name:
Fenuron
EC Number:
202-941-4
EC Name:
Fenuron
Cas Number:
101-42-8
Molecular formula:
C9H12N2O
IUPAC Name:
fenuron
Test material form:
other: white to off-white powder
Details on test material:
- Particle size distribution: 100 % particle size < 12 µm (method: Laser Diffraction; Certificate of Analysis)
Particle size parameter determined with a Malvern Mastersizer 2000 (Non-GLP determination)
D10% = 1.18 µm
D50% = 7.72 µm
D90% = 16.00 µm
D: Diameter; 10, 50, 90: percentage cumulative
- Mass median aerodynamic diameter (MMAD): 1.595 µm
- Geometric standard deviation (GSD): calculated as 2.09
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Isochem Kautschuk GmbH, Batch no. 0010416
- Expiration date of the lot/batch: April 2019
- Purity test date: 5 october 2017

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material : at room temperature (+10°C to +25°C) in a tightly closed container in a dry, cool and well-ventilated place, avoiding exposure to sunlight and moisture

OTHER SPECIFICS: IsoQure UR 300

Test animals

Species:
rat
Strain:
other: CD / Crl:CD(SD)
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, Germany
- Age at study initiation:
Males:approx. 8 weeks
Females:approx. 10 weeks
- Weight at study initiation:
Males:276 - 290 g
Females:230 - 250 g
-Housing: Granulated textured wood (Granulat A2, J. Brandenburg, 49424 Goldenstedt, Germany) was used as bedding material for the cages. The cages were changed and cleaned twice a week. During the 14-day observation period the animals were kept singly in MAKROLON cages (type III plus).
- Diet (e.g. ad libitum): Commercial diet, ssniff® R/M-H V1534 served as food. Feeding was discontinued approximately 16 hours before administration.
- Water: tap water ad libitum. Drinking water is examined according to the 'Deutsche Trinkwasserverordnung 2001' [German Regulations on drinking water 2001] by the Hamburger Wasserwerke, 20539 Hamburg, Germany, at least four times a year.
- Acclimation period: at least 5 adaptation days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): room temperature of 22°C ± 3°C
- Humidity (%): 55% ± 10%
- Photoperiod (hrs dark / hrs light): 12 hours each

IN-LIFE DATES:
From: Start of experimental phase: December 08, 2017
To: Termination of the in-life phase: January 29, 2018

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
air
Mass median aerodynamic diameter (MMAD):
1.595 µm
Geometric standard deviation (GSD):
2.09
Remark on MMAD/GSD:
The mass median aerodynamic diameter (MMAD) was estimated by means of non-linear regression analysis. The 10.6 µm particle size range and the filter
(particle size range < 0.55 µm) were not included in the determination of the MMAD in order not to give undue weight to these values.
The Geometric Standard Deviation (GSD) of the MMAD was calculated from the quotient of the 84.1%- and the 50%-mass fractions, both obtained from the above mentioned non-linear regression analysis.


Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: dynamic inhalation apparatus (RHEMA-LABORTECHNIK, 65719 Hofheim/Taunus, Germany) with cylindrical exposure chamber.
- Exposure chamber volume: 28.5 L
- Method of holding animals in test chamber: in pyrex tubes at the edge of the chamber in a radial position.
- Source and rate of air: compressed air (5.0 bar) from a compressor.
- Method of conditioning air: at the bottom of the exposure chamber, the air was sucked off at a lower rate than created by the dust generator in order to produce a homogenous distribution and a positive pressure in the exposure chamber (inflow 900 L/h, outflow 800 L/h). A manometer and an air-flow meter were used to control the constant supply of compressed air and the exhaust, respectively. Flow rates were checked hourly and corrected if necessary.
The oxygen content in the inhalation chamber was 21% v/v. It was determined at the beginning and at the end of the exposure with a DRÄGER Oxygen-analysis test set.
- System of generating particulates/aerosols: the dust of the test material was generated with a rotating brush dust generator
- Method of particle size determination: the impactor is a device that classifies particles present in a sample of air or gas into known size ranges. It does this by drawing the air sample through a cascade of progressively finer nozzles. The air jets from these nozzles impact on pre-weighed plane sampling surfaces (slides). Each stage represents an aerodynamic size range and collects finer particles than its predecessor. Each successive stage represents a special aerodynamic cut off diameter. The aerosol from the exposure chamber was drawn through the cascade impactor for 1 minute at a constant flow rate of 5 L/min. The slides were removed from the impactor and weighed on an analytical balance.
- Temperature, humidity, pressure in air chamber: the temperature (22°C ± 3°C) and humidity was checked and noted once every hour during the exposure period of the experiment.

TEST ATMOSPHERE
- Brief description of analytical method used: gravimetrically
- Samples taken from breathing zone: analysis of the dust concentration in the inhalation chamber was measured 4 times gravimetrically with an air sample filter (Minisart SM 17598; 0.45 µm) and pump (Vacuubrand, MZ 2C ) controlled by a rotameter. Dust samples were taken once every hour during the exposure. For that purpose, a probe was placed close to the animals' noses in the inhalation chamber and air was sucked through the air sample filter at a constant flow of air of 5 L/min for 1 minute. The filters were weighed before and after sampling on an analytical balance (accuracy 0.1 mg).


Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
5.06 mg/L air (actual concentration)
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: careful clinical examination at least once daily until all symptoms subsided; individual body weights of animals were
determined 1 day before administration (acclimatization period), on test day 1 prior to exposure and on test days 2, 4, 8, and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights (lungs)

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.06 mg/L air
Based on:
test mat.
Remarks:
99.0% analytical purity
Exp. duration:
4 h
Mortality:
No animal died
Clinical signs:
other: Slight dyspnoea immediately until 3 hours after end of exposure.
Body weight:
No influence on body weight gain was observed.
Gross pathology:
No pathological findings were noted at necropsy

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Under the present test conditions, the LC50 value for rats following inhalation of IsoQure UR 300 for 4 hours was determined as follows (actual concentration, mean aerosol concentration): LC50 males and females combined (14 days): > 5.06 mg IsoQure UR 300/L air/4 hours (actual concentration).
Executive summary:

The aim of the present study was to assess the acute inhalation toxicity of the test item IsoQure UR 300 when administered to rats for a single 4-hour period. Rats were exposed to IsoQure UR 300 at an actual concentration of 5.06 mg IsoQure UR 300/L air for 4 hours by inhalation using a dynamic nose-only exposure chamber. In the inhalation chamber, close to the animals' noses, the generated dust had a mass median aerodynamic diameter (MMAD) of 1.595 µm as determined with a cascade impactor. The Geometric Standard Deviation (GSD) of the MMAD was calculated as 2.09. A 4-hour exposure to IsoQure UR 300 at the concentration of 5.06 mg/L air revealed slight dyspnea immediately until 3 hours after end of exposure. No animal died prematurely. No influence on body weight gain was observed. No pathological findings were noted at necropsy. LC50 value for males and females combined (14 days): > 5.06 mg IsoQure UR 300/L air/4 hours.

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