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Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2007-02-09 to 2007-02-28
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP and guideline compliant study.

Data source

Referenceopen allclose all

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

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
(1992)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Version / remarks:
(1992)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Version / remarks:
(1998)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), Guidelines for Preparation of Study Results, Acute Inhalation Toxicity Studies Guideline 2-1-3. Notification 12 NohSan No. 8147 (2005)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
2-hydroxy-N,N-dimethylpropanamide
EC Number:
609-066-0
Cas Number:
35123-06-9
Molecular formula:
C5H11NO2
IUPAC Name:
2-hydroxy-N,N-dimethylpropanamide
Test material form:
other: Liquid

Test animals

Species:
rat
Strain:
other: HanRcc:WIST(SPF)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd, Laboratory Animal Services, CH-4414 Füllinsdorf, Switzerland
- Age at study initiation: Males: 9 weeks; Females: 10 weeks
- Weight at study initiation: Males: 237.6 g - 255.2 g; Females: 204.9 g - 211.4 g
- Fasting period before study: No data
- Housing: Group of five in Makrolon® type-IV cages with wire mesh tops and standard softwood bedding
- Diet: Pelleted standard Kliba-Nafag 3433, rat maintenance diet, ad libitum
- Water: Tap-water from Füllinsdorf, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 20 ± 1°C
- Humidity: 30 to 70%
- Air changes: 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light / 12 hours darkness

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION

- Exposure apparatus: Flow-past exposure chamber
- Exposure chamber volume: 12.0 L/min
- Method of holding animals in test chamber: Confined separately in restraint tubes, using a system similar to that originally described by Sachsse et al. (1973, 1976)
- Source and rate of air: The exposure airflow rate was recorded nine times during the inhalation exposure period, i.e. at 30 minute intervals from the start to the end of the inhalation exposure. The total airflow was maintained at 12.0 L/min.
- Method of conditioning air: No extra diluent air was added. The airflow rate of the aerosol as it arrived at the animal ports was 0.92 L/min/animal port.
- System of generating particulates/aerosols: Test aerosol was generated in ambient conditions using a nebuliser connected to a syringe pump.
- Method of particle size determination: Mercer 7 stage cascade impactor
- Treatment of exhaust air: The exhaled air is extracted through the gap near each feed tube leaving the exposure chamber via its outer cylinder followed by the extraction tube.
- Temperature, humidity: Temp: ~21°C; Hum: ~2.1%

TEST ATMOSPHERE

Test concentration:
Samples from the test aerosol were collected four times during exposure on pairs of Whatman GF/C glass fiber filters. For aerosol sampling each filter was loaded in a 47 mm in-line stainless steel filter sampling device. For gravimetric determination of aerosol concentration the filters were carefully weighed before and after sampling using a Mettler MX5 analytical balance.
For chemical analysis the filters were put into an appropriate, umber coloured glass vial and covered with 10 mL of chloroform to minimise possible loss of test item by evaporation from the filter.
The filter samples were analysed by gas chromatography (GC) with flame ionisation detection (FID).

Temperature/Relative humidity
The temperature and relative humidity were continuously monitored and recorded for the duration of the exposure period using a calibrated VAISALA HMI 32 humidity and temperature indicator (Kuenzli Elektronik, CH-8006 Zürich, Switzerland), connected to an analogue chart recorder. The results are reported at 30 minute intervals from the start to the end of the inhalation exposure.

Oxygen concentration
The oxygen concentration was continuously monitored and recorded for the duration of the exposure period using a calibrated Oxopac RD device (Dräger AG, CH-8305 Dietlikon, Switzerland) connected to an analogue chart recorder. The results are reported at 30 minute intervals from the start to the end of the inhalation exposure.

- Samples taken from breathing zone: Yes

- Particle size distribution: The particle size distribution was determined twice during the exposure using a Mercer 7 stage cascade impactor, flow rate of 1.0 L/min and the particles deposited according to their aerodynamic size onto stainless steel slips and the final filter stage on each stage of the impactor. To obtain the mass deposited on each stage of the impactor, the steel slips and the final filter stage were carefully weighed before and after sampling.
The total mass (μg) deposited in the impactor was then calculated by adding together the mass deposited on each of the stainless steel slips and the final filter stage. As the Effective Cut-off Diameters (ECD) represent the lower size limit of the particles collected on each stage, the percentages less than the indicated size were tabulated as a function of the ECD.

- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): Cumulative percent values were used to calculate the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) using Microsoft Excel software. The target range for the mass median aerodynamic diameter was 1 to 4 μm.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
The nominal aerosol concentration attained over the entire 30 minute pre-exposure aerosol generation and 4 hour exposure period amounted to 5.383 mg/L air.
No. of animals per sex per dose:
5 males and 5 females
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: Prior to exposure on test day 1, and during the observation period on test days 4, 8 and 15.
- Necropsy of survivors performed: Yes on day 15, all animals were sacrificed and necropsied.
- Other examinations performed: Clinical signs, macroscopic pathology

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LC50
Effect level:
5.004 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: (chemically determined mean aerosol concentration equivalent to a gravimetrically determined mean aerosol concentration of 5.226 mg/L air).
Mortality:
No spontaneous deaths occurred in this study.
Clinical signs:
other: Examination of each animal during and after exposure did not reveal any clinical signs during the 15-day observation period.
Body weight:
Body weight loss, marginal in degree, or retardation in body weight gain was evident in four of five male animals (nos. 1, 3, 4 & 5, mean weight change in the affected males –0.2%) and body weight loss, moderate to marked in degree, in all of five female animals (nos. 6 to 10, mean weight loss in the females –6.7%) over the first three days following the inhalation exposure (test days 1 to 4). During the remainder of the 15-day observation period all animals gained body weight normally.
A relationship of these, transient effects on body weight to the treatment with the test item could not be entirely discounted, although there were no clinical signs or other indications of toxicity during this study and slight physical stress, e.g. during restraint in the exposure tubes, may have contributed to these effects.
Gross pathology:
Examination of each animal on the scheduled day of necropsy (test day 15) did not reveal any macroscopic findings.

Applicant's summary and conclusion

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