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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:
weight of evidence
Study period:
1989-03-30 through 1989-04-12
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Acceptable, well-documented study report which meets basic scientific principles. Original report available as copy. Restriction: low number of animals, short observation period. Only 2 dose levels tested. Restriction acceptable because of low test substance volatility. No data on gross pathology. Read-across justification: The substance is hydrolytically unstable. When it comes in contact with water or moisture complete hydrolysis will take place with no significant reaction products other than alcohol and hydrated titanium dioxide. This rapid hydrolysis (hydrolysis half-life < 3 minutes to < 2 hours) is the driving force for the toxicokinetics of target substance. Because of the rapid hydrolysis, the influence of the mode of administration through inhalation, dermal and oral is related to the hazardous degradation product (alcohol) released from the target substance. The identification of degradation products from the hydrolysis study conducted for the target substance verifies that there are no impurities in the alcohol released from the target substance, which might change the hazardous properties of the target substance compared to the properties of the pure alcohol. As there is a mechanistic reasoning to the read-across, the unnecessary animal testing is avoided by using the read-across data from the degradation product (relevant alcohol) to evaluate irritation, sensitization and the short term and long-term toxicological effects and mutagenicity of the target substance.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989
Report Date:
1989

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
only 2 dose levels; low animal numbers; 7 day observation period
Principles of method if other than guideline:
Method: similar to OECD 403 with restrictions: 2 dose levels tested. 3 animals per sex and dose level were tested. Test atmosphere concentration and particle size was determined. Observation period was 7 days.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): C-1257
- Physical state: clear liquid
- Analytical purity: 99.5%
- Storage condition of test material: cool ventilated cabinets or fume hoods

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Raleigh, North Carolina
- Age at study initiation: Group I Group II
Males 8 weeks 9 weeks
Males 9 weeks 11 weeks

- Weight at study initiation: Group I Group II
Males: range: 230-238 g; 350-335 g
mean: 235g 353g
Females: range: 221-228 g; 250-265 g
mean: 225g 258g



- Fasting period before study:
- Housing: in stainless steel wire mesh cages; in groups of 2 during the first week of acclimatisation; singly thereafter
- Diet (e.g. ad libitum): standard laboratory diet (Purina Rodent laboratory Chow Brand Animal Diet #5001)
- Water (e.g. ad libitum): automated watering system
- Acclimation period: 1 week (Group I) and 3 weeks (Group II)


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 67-76°F
- Humidity (%): 40-70%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12hrs dark/12 hrs light

Administration / exposure

Route of administration:
other: Group I: vapour + aerosol; Group II: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Plexigla / glass exposure chamber
- Exposure chamber volume: 100 L
- Method of holding animals in test chamber: animals were caged
- Source and rate of air: house-supply air
- System of generating particulates/aerosols:
Group I: the test material was placed into a 250 mL Erlenmeyer flask from where it was delivered by a fluid metering pump into the fluid inlet of an air atomizing nozzle. House-supply air was delivered through the air inlet to the atomizer to generate the aerosol which was directed into the exposure chamber.
Group II: air was drawn through 2 glass bubblers, place in water bath in tandem, which contained the test material. The air was heated to 50°C in the first and 30°C in the second bubbler; the air was then directed to a 3-neck flask containing glass wool before the filtered air was directed to the exposure chamber.

- Method of particle size determination:
Group I: once during exposure using a Delron DCI-6 Cascade Impactor.
Group II: hourly during exposure using a TSI Aerodynamic Particle Sizer (Model 3300)



TEST ATMOSPHERE
- Brief description of analytical method used:
Group I: gravimetric determination of test material drawn from the breathing zone onto glass microfibre filter paper followed by a charcoal tube. The gravimetric concentration (aerosol/vapour/total) was calculated by dividing the weight difference in mg by the volume of air sampled in L.

Group II: hourly samples were drawn and directed to a IRAN 1A Ambient Air Analyzer. The exposure level was determined from the absorbance using a calibration curve constructed using the same equipment.

- Samples taken from breathing zone: yes


VEHICLE
- Composition of vehicle (if applicable): air
- Concentration of test material in vehicle (if applicable): none


TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: Group I: 81% of particles < 10 microns
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): Group I: 5.6 microns (geometric st. dev. 1.9)
Group II: no aerosol formation was considered, due to very low levels of particulates (0.015 mg/m³)

Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
0.89 mg/L (vapour) and 5.3 mg/L (mixed vapour and aerosol)
No. of animals per sex per dose:
3
Control animals:
other: historical controls
Details on study design:
- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: viability was assessed twice daily. Body weights were determined on days 1 (immediately prior to exposure) and on day 8 (prior to sacrifice).
- Necropsy of survivors performed: no
Statistics:
none

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 0.89 - <= 5.3 mg/L air
Exp. duration:
4 h
Remarks on result:
other: 0.89 mg/L (vapour); 5.3 mg/L (mixed vapour and aerosol)
Mortality:
Group I: all animals died (6/6)
Group II: no animals died (0/6)
Clinical signs:
Group I: 4 animals died during the exposure period or shortly thereafter. Observations included laboured breathing, nasal discharge, prostration, and closed eyes.
Body weight:
Group I: 4 animals died during the exposure period or shortly thereafter.
Group II: decreased activity was noted during exposure; after the exposure the animals were unremarkable, and most gained weight during the following week.
Gross pathology:
No data

Any other information on results incl. tables

The proportion of inspirable aerosol was high in the first experiment with Group I, and there was a large discrepancy between the measured and the nominal concentration which was calculated from the amount of test material consumed during the exposure.

Group

Concentration (mg/L)

aerosol

vapour

total

nominal

         I      

4.3

1.1

5.3

43

II

-

0.89

0.89

2.5

The vapour saturation concentration was calculated to be 1.4 mg/L at 20°C, based on the vapour pressure of 0.2 mm Hg.

Applicant's summary and conclusion

Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LC50 was > 890 mg/m3. The complete mortality in the first experiment was attributed to the high proportion of respirable aerosol.
Executive summary:

Following the 4 hour inhalation exposure to 0.89 mg 2-EH/m3 no mortalities or clinical signs of toxicity were noted in male and female Sprague-Dawley rats within the 7-day observation period.

In contrast, all animals of the 5 mg/L target concentration group died, 4 of them during the exposure or shortly thereafter. It was, however, demonstrated that only 20% of the measured concentration was attributable to vapour whereas 80% was represented by particulates. The majority of the particulates (81%) had a mean aerodynamic diameter of 10 µm and were thus respirable by rats. The measured concentration was only 12.3% compared to the nominal concentration which was calculated from the consumed test material.

Based on the above it is concluded that the 4 -hour LC50 in rats was > 0.89 mg/m3. The vapour saturation concentration was calculated to be 1.4 mg/L at 20°C, based on the vapour pressure of 0.2 mm Hg (BioDynamics, 1989).