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Toxicological information

Acute Toxicity: inhalation

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Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labelling and/or risk assessment. This study is used for read-across and therefore has been assigned a reliability of 2 (reliable with restrictions). Otherwise the study has a reliability of 1 (reliable without restriction).

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report Date:
2009

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
Remarks:
The study was conducted according to guideline in effect at time of study conduct.
Qualifier:
according to
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Deviations:
no
Remarks:
The study was conducted according to guideline in effect at time of study conduct.
Qualifier:
according to
Guideline:
other: EEC Methods for the Determination of Toxicity Method B.2 Directive 92/69/EEC
Deviations:
no
Remarks:
The study was conducted according to guideline in effect at time of study conduct.
Qualifier:
according to
Guideline:
other: MAFF Japan Agricultural Chemicals Regulation Laws 2-1-3 Notification 12 Nousan 8147 and Notification 13 Seisan 1739
Deviations:
no
Remarks:
The study was conducted according to guideline in effect at time of study conduct.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Purity: 99.7%

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: approximately 8 or 9 weeks
- Weight at study initiation: Males (271-354 grams); Females (192-249 grams)
- Fasting period before study: None
- Housing: Except during exposure, animals were individually housed in solid bottom caging with bedding
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-26°C
- Humidity (%): 30-70%
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12 h light/12 h dark

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Glass (cylindrical). A dispersion plate inside the chamber promoted uniform chamber distribution of the test atmosphere.
- Exposure chamber volume: 34 L (nominal internal volume)
- Method of holding animals in test chamber: Animals were individually restrained in perforated stainless steel cylinders with conical nose pieces. The restrainers were inserted into a polymethylmethacrylate faceplate attached to the exposure chamber so that the nose of each animal extended into the exposure chamber
- Source and rate of air: houseline air; at least 7 air changes per hour.
- Method of conditioning air: Chamber oxygen concentration was targeted to be at least 19%.
- System of generating test atmosphere: For the 0.65, 1.7, and 5.2 mg/L exposures, chamber atmospheres were generated by flash evaporation of the test substance in air with a heated glass mixing flask. The test substance was metered into the mixing flask with a syringe infusion pump. The mixing flask was heated to approximately 200°C to vaporise the test substance. High-pressure air, metered to the mixing flask by a mass flow controller, carried the resulting vapour into glass tubing that led to the exposure chamber. A second mass flow controller metered dilution air to the mixture and carried the atmosphere to the exposure chamber through a glass baffle. For the 9.9 mg/L exposure, chamber atmospheres were generated by atomisation of the test substance in air with a nebuliser. The test substance was metered into the nebuliser with a syringe infusion pump. High-pressure air, metered into the nebuliser by a mass flow controller, carried the resulting atmosphere into the exposure chamber. The mixing flask, mass flow controllers, and infusion pumps were controlled and monitored by the Inhalation Toxicology Automated Data System. Chamber concentrations of test substance were controlled by varying the test substance feed rate to the mixing flask.
- Method of particle size determination: Samples to determine particle size distribution (mass median aerodynamic diameter, geometric standard deviation, and percent particles less than 1, 3, and 10 μm diameter) were taken twice during each of the 5.2 and 9.9 mg/L exposures with a cyclone preseparator/cascade impactor and a constant flow air sampler.
- Treatment of exhaust air: Exhausted through a dry-ice cold trap prior to discharge into the fume hood.
- Temperature, humidity, pressure in air chamber: 20 to 25°C; 48-56%; pressure not reported.
- Air flow rate: 16L/min
- Air change rate: Not reported.

TEST ATMOSPHERE
- Brief description of analytical method used: Gravimetric analysis and gas chromatography (GC) of the aerosol and vapour concentrations, respectively.
- Samples taken from breathing zone: yes
- Mean Concentration and Particle Size Distribution: The mean concentrations for the 4 exposures were 0.65, 1.7, 5.2 and 9.9 mg/L based on combined vapour and aerosol concentrations. Significant aerosol was not present at the 0.65 and 1.7 mg/L concentrations. At the 5.2 and 9.9 mg/L concentrations, there was 1.6 and 7.1 mg/L of aerosol present in the respective chamber atmospheres. The mean mass median aerodynamic diameters (MMAD) determined from 2 samples collected during each of the 5.2 and 9.9 mg/L experiments were 6.5 and 3.8 μm, respectively. The large difference between the 2 MMADs was related to means of generation of the 2 test atmospheres. In the 5.2 mg/L experiment, the test substance liquid was flash evaporated and a condensation aerosol was formed in the chamber atmosphere, while in the 9.9 mg/L experiment, the test liquid was sprayed forming smaller droplets.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
0.65, 1.7, 5.2 and 9.9 mg/L (mean) based on combined vapour and aerosol concentrations.
There was no appreciable aerosol (approximately <0.1 mg/m³) present in the 0.65 and 1.7 mg/L chambers. At the 5.2 and 9.9 mg/L concentrations, there was 1.6 and 7.1 mg/L of aerosol present in the respective chamber atmospheres.
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Animals were observed for mortality and response to alerting stimuli during each exposure and observed for mortality and clinical signs of toxicity immediately after they were removed from the restrainers following exposure. During a 14-day recovery period, all surviving rats were observed each day for mortality, and were weighed and observed for clinical signs of toxicity throughout the recovery period. At the end of the recovery period, all surviving rats were sacrificed by carbon dioxide asphyxiation and subjected to gross pathology examination.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.2 - < 9.9 mg/L air
Exp. duration:
4 h
Remarks on result:
other: Subsequent Probit analysis of the results listed in this acute inhalation study yielded a 4-hour LC50 in rats of 7.2 mg/L total (5.2 mg/L aerosol). The 5.2 mg/L value will be used for purposes of classification and labelling.
Mortality:
No rats died after the 5.2 mg/L exposure, and all rats died as a result of the 9.9 mg/L exposure.
Clinical signs:
other: At the non-lethal concentrations (0.65, 1.7, and 5.2 mg/L), ocular or nasal discharges were observed in most male rats after exposure and in 1, 3, and 5 females at each of the concentrations. There was also alopecia observed in one male and one female rat
Body weight:
One day following the 0.65 and 1.7 mg/L exposures, slight (<5 %), weight reductions, occurred in most male rats and in 2/5 and 3/6 female rats, respectively. By 2 days post exposure, all rats showed body weight gains. At 5.2 mg/L, slight weight losses were observed in male rats one day after exposure, followed by an essentially normal weight gain. The female 5.2 mg/L rats had all resumed a normal weight gain by the 7th day after exposure. At 9.9 mg/L, all rats were severely affected, with weight losses among the survivors at >10% one day after exposure followed by continuous weight loss until lethality occurred.
Gross pathology:
Gross discoloration of the lungs was present in most of the male and female rats in the 9.9 mg/L group. This is a nonspecific finding commonly observed in early death animals. All other gross findings occurred in low (most single) incidences and/or are common findings in rats of this strain and age.

Any other information on results incl. tables

Subsequent Probit analysis of the results listed in this acute inhalation study yielded a 4-hour LC50 in rats of 7.2 mg/L total (5.2 mg/L aerosol). The 5.2 mg/L value will be used for purposes of classification and labelling.

Applicant's summary and conclusion

Interpretation of results:
study cannot be used for classification
Remarks:
Migrated information
Conclusions:
LC50 > 5.2 mg/L and < 9.9 mg/L
The study and the conclusions which are drawn from it fulfil the quality criteria (validity, reliability, repeatability).
Executive summary:

Groups of 5 male and 5 female Crl:CD(SD) rats were exposed nose-only for a single, 4-hour period to test substance vapour or vapour/aerosol mixtures in air. After exposure, surviving rats were weighed and observed for clinical signs of toxicity during a 14-day recovery period. Mean exposure concentrations, determined by gas chromatography and by gravimetric measurement were 0.65, 1.7, 5.2, or 9.9 mg/L (combined aerosol/vapour). At the 5.2 and 9.9 mg/L concentrations, there was 1.6 and 7.1 mg/L of aerosol present in the respective chamber atmospheres. There was no appreciable aerosol (approximately <0.1 mg/m³) present in the 0.65 and 1.7 mg/L chambers. All rats died from one to 6 days after exposure at 9.9 mg/L. No deaths occurred at the other 3 exposure concentrations.

Slight weight losses (<5%) occurred in rats exposed to 0.65, 1.7, and 5.2 mg/L, while severe weight losses (>10%) occurred in rats exposed at 9.9 mg/L. At the non-lethal concentrations (0.65, 1.7, and 5.2 mg/L), ocular or nasal discharges were observed in most male rats after exposure and in 1, 3, and 5 females at each of the concentrations, respectively. There was also alopecia observed in one male and one female rat. These are common findings in rats while under restraint in inhalation studies. Other sporadic findings included wet fur in one female rat in the 5.2 mg/L group. At the lethal concentration (9.9 mg/L), laboured breathing was observed in all rats.

Since no rats died after the 5.2 mg/L exposure, and all rats died as a result of the 9.9 mg/L exposure, the 4-hour inhalation median lethal concentration (LC50) was > 5.2 mg/L and < 9.9 mg/L. Subsequent Probit analysis of the results listed in this acute inhalation study yielded a 4-hour LC50 in rats of 7.2 mg/L total (5.2 mg/L aerosol). The 5.2 mg/L value will be used for purposes of classification and labelling.