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Acute Toxicity: inhalation

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Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
15 Aug 2011 - 13 Dec 2011
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report date:
2012

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
2009
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Version / remarks:
2008
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Version / remarks:
1998
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Constituent 1
Reference substance name:
Dimethyl(propyl)amine
EC Number:
213-139-9
EC Name:
Dimethyl(propyl)amine
Cas Number:
926-63-6
Molecular formula:
C5H13N
IUPAC Name:
N,N-dimethylpropan-1-amine
Constituent 2
Reference substance name:
Dimethyl-n-propylamine
IUPAC Name:
Dimethyl-n-propylamine
Test material form:
other: liquid
Details on test material:
- Name of test material (as cited in study report): Dimethyl(propyl)amine
- Physical state: liquid, colourless, clear
- Analytical purity: 99.9%
- Purity test date: 27 Aug 2010 (BASF SE, Competence Center Analytics, Report 10L00219, 2010)
- Lot/batch No.:000STD77L0
- Stability under storage conditions over the study period: guaranteed by the sponsor, and the sponsor holds this responsibility.
- Storage condition of test material: room temperature, under N2

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Strain as cited in the study report: RccHan:WIST
- Source: Harlan Laboratories B.V., Horst, Netherlands
- Age at study initiation: males, 8 to 9 weeks; females, 10 to 11 weeks
- Mean group weight at study initiation:
- - Males: group 1, 240 g; group 2, 273 g; group 3, 234 g
- - Females: group 1, 182 g; group 2, 186 g; group 3, 188 g
- Housing: Makrolon cages type M III (floor area about 800 cm2) for single housing; Polysulfon cages (floor area about 2065 cm2) for group caging (up to 5 animals/cage) if the animals were free from clinical signs and findings.
- Diet: Kliba-Labordiet (Maus/Ratte Haltung “GLP”; Provimi Kliba SA, Kaiseraugst, Basel, Switzerland), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes: 15 per hour
- Photoperiod (hrs dark/hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose/head only
Vehicle:
clean air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE
- A central air conditioning system provided cold air of about 15°C, which was passed through an activated charcoal filter, adjusted to room temperature, and passed again through a second particle filter (H13 (HEPA) Camfil Farr, Germany). The air was compressed (oil-free compressor) by filtering through an inlet air strainer and introducing into the compressor. After passed through an second ultra filter, the compressed, 15 bar air was stored in a storage of 1500 or 5000 L. The compressed air was conducted to the labs via pipes, where the pressure was reduced to 6 bar; in the laboratory, it was then used to generate the inhalation atmospheres.

GENERATION OF TEST ITEM VAPOURS
For each test group the vapours were generated by supplying amounts of the unchanged test substance to a heated vaporizer (glasses with thermostat, 50 °C) by means of a piston metering pump. The vapours that developed were taken up by the supply air and passed into the exposure system.

INHALATION CHAMBER
Head-nose inhalation system INA 60 (glass-steel construction, BASF SE, volume V ˜ 90 L): the animals were restrained in glass tubes and their snouts projected into the inhalation system. The exhaust air was filtered and conducted into the exhaust air of the building. The exposure system was located inside an exhaust cabin in an air-conditioned laboratory. During each exposure, the following parameters were recorded four times at about 1-hour intervals: continuous measurement of compressed air flow supply, with adjustment; continuous measurement of exhaust air flow, with adjustment. The lower amounts of exhaust air, which were adjusted by means of a separate exhaust air system, achieved positive pressures inside the exposure systems. This ensured that the mixtures of test substance and air were not diluted with laboratory air in the breathing zones of the animals.

TEST ATMOSPHERE ANALYSIS
The nominal concentrations of the test item vapours were calculated from the amounts of test item dosed and the supply air flows.
For determination of the concentration of the test item in the inhalation atmosphere, the test atmosphere sample volumes were adjusted to achieve suitable amounts of the test item in the samples of the test groups in reference to the calibration of the analytical method. 2-Propanol was used as sorption solvent and was contained in 3 absorption vessels connected in series. The contents of the first 2 vessels were pooled and analyzed for each sample; the third vessel was used to control the effectiveness of the sorption for all samples of the atmosphere and was analyzed separately at the end of the sampling campaign. Sampling was done immediately adjacent to the animals' noses at a separate spare port.
Sampling flow was 1 L/minute and sampling frequency was 4 at hourly intervals.

OXYGEN, TEMPERATURE AND HUMIDITY MONITORING
Since the air change (at least 33 times/hour, calculated by dividing the supply air flows by the volume of the inhalation chamber) was judged to be sufficient to prevent oxygen depletion by the breathing of the animals, no monitoring of oxygen content was done. The temperature in the inhalation chambers was measured continuously. The humidity in the inhalation chambers was measured with a dielectric probe.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
Analysis was done by gas chromatography (for details, see above)
Duration of exposure:
4 h
Concentrations:
measured: 0.479 (test group 1), 2.303 (test group 2) and 5.073 (test group 3) mg/L air
No. of animals per sex per dose:
Five
Control animals:
no
Details on study design:
DURATION OF OBSERVATION PERIOD
14 days
FREQUENCY OF OBSERVATIONS FOR MOTALITY AND CLINICAL SYMPTOMS
A check for any dead or moribund animal was made twice each workday and once on Saturdays, Sundays and on public holidays. Detailed clinical observations were recorded for each animal separately several times during exposure and at least once daily on the pre-exposure day and during the observation period.
FREQUENCY OF WEIGHING
Individual body weights were recorded 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.
NECROPSY
At the end of the observation period the surviving animals were sacrificed with CO2-inhalation and were subjected to gross pathological examination as well as the animal which died before.
Statistics:
The LC50 was calculated by Probit analysis (Finney DJ, "Probit Analysis" Cambridge University Press, 1971); for results of the type ”LC50 greater than”, ”LC50 approx.”, or ”LC50 smaller than”, the binomial test was used for statistical evaluation (Steel RGD and Torrie JH, Principles and procedures of statistics a biometrical approach. McGraw - Hill, 1984)

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
4.499 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: 0% mortality at 0.479 mg/L, 0% mortality at 2.303 mg/L, 90% mortality at 5.073 mg/L
Mortality:
No mortality occurred at the tested concentrations of 0.479 and 2.303 mg/L air.
At 5.073 mg/L air, 4/5 males and 5/5 females died during and after exposure (day 0), resulting in 90% mortality at the highest concentration level tested in this study.
Clinical signs:
other: Clinical signs of toxicity in animals exposed to 0.479 mg/L comprised piloerection and substance contaminated fur. These various findings were observed after exposure on study day 0. No clinical signs and findings were observed from study day 1 onwards.
Body weight:
The mean body weights of the animals exposed to 0.479 mg/L decreased during the first post exposure observations day and increased from study day 3 onward.
The mean body weights of the animals exposed to 2.303 mg/L decreased during the first post exposure observations day and increased from study day 3 onward.
In the 5.073 mg/L group, the body weight of the male animal surviving the exposure period decreased during the first post exposure observations day and increased from study day 3 onward.
Gross pathology:
In animals exposed to 0.479 mg/L, necropsy revealed no gross pathological abnormalities.
In animals exposed to 2.303 mg/L, necropsy revealed no gross pathological abnormalities.
In animals exposed to 5.073 mg/L, necropsy of those animals that died (4 males, 5 females) revealed edema of the lung in only one female; necropsy of the remaining animals as well as of the male survivor revealed no gross pathological abnormalities.

Any other information on results incl. tables

Analytical monitoring of temperature and humidity:

Test Group

Mean Temperature (°C)

Mean relative humidity (%)

Group 1, 0.479 mg/L

28.0 ± 0.9*

55.3 ± 5.0

Group 2, 2.303 mg/L

23.1 ± 0.2

54.1 ± 2.1

Group 3, 5.073 mg/L

23.8 ± 0.3

67.8 ± 0.4

*, The mean temperature above the range given in the guidelines resulted from the technical need to use high generation temperature to reach the desired concentrations.

Applicant's summary and conclusion

Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
CLP: Acute Inhalation Category 3, H331
Executive summary:

Dimethyl-n-propylamine was investigated for acute inhalation toxicity in a study conducted with Wistar rats according to the OECD TG 403 (2009). The study conduct followed GLP. Groups of five male and five female rats were head - nose exposed during 4 hours to following measured concentrations of the test item vapour: 0.479, 2.303 and 5.073 mg/L air. In fact, the animals were exposed to the inhalation atmosphere for 4 hours plus equilibration time of the inhalation systems (t99 minimum 4 min).

Whereas no mortality was observed at the 2 lowest tested concentrations of 0.479 and 2.303 mg/L air, 90% mortality (4/5 males, 5/5 females) was reached at the highest test concentration of 5.073 mg/L air during and shortly after exposure. Clinical signs were observed in all 3 groups, lasting for up to 1 day following exposure; these signs comprised e.g., piloerection, substance contaminated fur, accelerated respiration, labored and intermittent respiration, abdominal respiration, red encrusted nose. The mean body weights of the animals decreased during the first post exposure observations day and increased from study day 3 onward. Necropsy was inconspicuous, except for one died female showing lung edema. The LC50 for male and female rats was estimated to be 4.5 mg/L air.