2-propanol and 2-butanol production, distn. residues

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

28 May 2010 - 14 June 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

Study under GLP, according to international guidelines and with full documentation

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2010

Report date:

2010

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

2-propanol and 2-butanol production, distn. residues, sample 2010

Molecular formula:

UVCB substance

IUPAC Name:

2-propanol and 2-butanol production, distn. residues, sample 2010

Test material form:

liquid

Details on test material:

- The analysis was performed for the reference sample "Sample 2010" as defined in Section 1.4
- Lot/batch No.: 10013593
- Expiration date of the lot/batch: March 2011
- Storage condition of test material: For several days, the test item was stored in the test facility at room temperature protected from light and kept under inert gas. As soon as a fridge with explosion prevention was available, the test item was stored at 2 – 8 °C. No relevant changes in composition were detected before and after storage at room temperature (GC chromatograms).

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
Species / Strain: Rat, CRL (WI) BR of Wistar origin
Source: Toxi-Coop Zrt. 1103 Budapest, Cserkesz u. 90.
Hygienic level: SPF at arrival and kept in good conventional environment during the study.
Age of animals at arrival: Young adult rats, 7 - 9 weeks old
Body weight range at treatment: Male: 278 - 306 g; Female: 196 - 214 g
Number of animals: 5 male and 5 female (nulliparous and non pregnant animals) rats
Number of animals/group: 5 animals/ sex
Acclimatisation time: 15 days
Acclimatisation to the test apparatus: 11 days
- Fasting period before study: no
- Housing: Group caging (2 or 3 animals, by sex, per cage)
- Diet (e.g. ad libitum): The animals received ssniff® SM R/M-Z+H complete diet produced by ssniff Spezialdiäten GmbH, D-59494 Soest Germany, ad libitum.
- Water (e.g. ad libitum): Animal received tap water from watering bottles.

Environmental conditions:
Illumination: Artificial light, from 6 a.m. to 6 p.m.
Temperature: 22 ±3 °C
Relative humidity: 30 - 70%
Ventilation: 8 - 12 air exchanges/hour by central air-condition system. Environmental conditions were maintained by an air-condition system. Temperature and relative humidity were verified and recorded daily during the study.

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

nose only

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: anodised aluminium Flow Past Exposure Chamber (CR Equipment SA, Switzerland)
- Exposure chamber volume: 6 L
- Method of holding animals in test chamber: polycarbonate restraining tubes
- Source and rate of air: rate: Source: no data; 1.0 L/min
- Method of conditioning air: The air was supplied by an oil-free air compressor and was filtered in a two-stage filter set (Festo: 1 μm and 0.01 μm). The temperature of the air was regulated by a heat exchanger. The air was not humidified in order to avoid modification of particle size distribution.
- System of generating particulates/aerosols: The test atmosphere was generated by a compressed air nebulizer (TSE Systems GmbH, Bad Homburg, Germany.) In the nebulizer the air flow rate was 15 L/min.
- Method of particle size determination: 7-stage cascade impactor type 02-150 (IN-TOX Products, N.M., USA)
- Treatment of exhaust air: no data
- Temperature, humidity, pressure in air chamber: 23.8 - 26.3 °C; 26.5 - 9.1 % relative humidity; pressure: no data

TEST ATMOSPHERE
- Brief description of analytical method used: The actual test atmosphere concentration was measured five times during exposure by pulling a volume of 10 L of test atmosphere (flow rate: 2.0 L/min) through sampling cylinders (length: 100 mm, dia. 30 mm) tightly filled with about 20 g of granulated activated carbon (Reanal Private Ltd., Prod. No. 29903-1-99-33, pellet diameter 4 mm). The amount of adsorbed test item was determined gravimetrically by the balance type Mettler PM100 (d = 1 mg).
- Samples taken from breathing zone: yes

VEHICLE
no vehicle used

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: see any other information on materials and methods
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.):
MMAD: Mass Median Aerodynamic Diameter (mean): 0.59 μm
GSD: Geometric Standard Deviation (mean): 1.35
Inhalable Fraction: Aerodyn. Diameter < 4 μm: 100 %

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration: upper limit of the classification into acute toxicity category 4 according to the CLP-regulation.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

method see above

Duration of exposure:

4 h

Remarks on duration:

nose-only exposure

Concentrations:

21.0 mg/L (Mean Achieved Concentration)

No. of animals per sex per dose:

5 males, 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Animals were checked twice daily during the observation period for morbidity and/or mortality.
All animals were observed for clinical signs at 1st, 2nd and 3rd hours during exposure, as soon as practicable following removal from restraint, one hour after exposure and subsequently once daily for fourteen days.
Individual bodyweights were recorded on the day of exposure Day 0 (prior to exposure) and Days 1, 3, 7 and 14.

- Necropsy of survivors performed: yes; At the end of the fourteen day observation period, the animals were euthanized by exsanguination under anaesthesia (intra-peritoneal injection of Euthasol® 40%) and gross necropsies were performed. These included a detailed examination of the abdominal and thoracic cavities with special attention given to the respiratory tract for macroscopic signs of irritancy or local toxicity.

- Other examinations performed: clinical signs, body weight

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 21 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No animal died during the study.

Clinical signs:

other: In all male and female animals were observed decreased activity and general reaction and incoordination after removal from restraint on completion of the exposure. In four female and in three male animals were found tremor at this time. One hour after the

Body weight:

In both genders of some animals body weight loss was observable on the day of inhalation exposure. In both sexes a compensation of body weight loss was found from third days of observation period.
On basis of body weight and body weight gain data, there was no notable test item effect observable in the exposed animals.

Gross pathology:

A single four hours nose-only exposure of reaction mass of 2,2'-oxybisbutane (DSBE), DIPE, SBA and 2-methylpropan-2-ol (TBA) to CRL: (WI) BR rat followed by a 14-day observation period at a dose level 21.0 mg/L was not associated with any test item-related macroscopic findings.

Any other information on results incl. tables

Test atmosphere concentrations

The test atmosphere concentration was sampled five times during the exposure. The actual concentration of the test item was calculated as the average of the concentrations obtained from gravimetry of the samples. The test item appeared as vapour, however, a small amount of aerosol was also detected in the cascade impactor. The aerosol particles presented approximately 0.04 % of the total mass of the test item in the test atmosphere.

Table 1

Mean Achieved Concentration	Standard Deviation	Aerosol Concentration	Nominal concentration
21.0 mg/L	2.21 mg/L	9.2 µg/L	26.1 mg/L

Individual Body weight data:

Sex	Animal Number	Body weight (g)						Weekly Increase (g)
		Day 0	Day 1	Day 3	Day 7	Day 14	Day 16	Week 1	Week 2
Male	5877	285	280	290	321	370	387	36	49
	5883	278	275	289	312	356	366	34	44
	5888	306	305	321	346	380	396	40	34
	5889	292	292	313	335	370	380	43	35
	5890	280	274	289	308	341	349	28	33
Mean:		288.2	285.2	300.4	324.4	363.4	375.6	36.2	39.0
*Difference in %			-1.0	5.3	8.0	12.0	3.4	12.6	12.0
Female	5905	206	204	217	231	248	255	25	17
	5912	200	200	210	222	245	250	22	25
	5914	213	223	233	248	276	272	35	28
	5917	214	219	221	229	255	258	15	26
	5918	196	191	201	211	227	224	15	16
Mean:		205.8	207.4	216.4	228.2	250.2	251.8	22.4	22.4
*Difference in %			0.7	4.3	5.5	9.6	0.6	11.0	9.6

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Under the experimental conditions of this study, no deaths occurred in a group of ten rats exposed for four hours to the atmosphere containing the test item at the mean achieved concentration of 21.0 mg/L. The acute inhalation median lethal concentration (4 hr LC50) of test item "2-propanol and 2-butanol production, distn. residues", in Wistar Crl:(WI) BR rats, was therefore considered to be greater than 21.0 mg/L.
The clinical signs represented the decreased activity and general reaction, tremor, incoordination and sleeping.
Consequently, "2-propanol and 2-butanol production, distn. residues" must not be classified for acute toxicity by inhalation.

Executive summary:

Acute inhalation toxicity of test item „2-propanol and 2-butanol production, distn. residues“ was tested under GLP and according to OECD 403 and EU B.2 guidelines. A group of ten Wistar Crl:(WI) BR rats (five males and five females) was exposed to an atmosphere that contained the vapour and in small fraction (0.04 %) the aerosol of the test item. The animals were exposed for four hours using a nose-only exposure system, followed by a fourteen day observation period. The mean achieved atmosphere concentration was 21.0 ±2.21 mg/L.

In all male and female animals test item related clinical signs were found after removal from restraint on completion of the exposure. One hour after the exposure all animals slept.

All male and female animals were symptom-free from first day of observation period. The clinical signs represented the decreased activity and general reaction, tremor, incoordination and sleeping. On the basis of body weight and body weight gain data, there was no notable test item effect observable in the exposed animals.

A single four hours nose-only exposure of the test item „2-propanol and 2-butanol production, distn. residues“ to CRL: (WI) BR rat followed by a 14-day observation period at a dose level 21.0 mg/L was not associated with any test item-related macroscopic findings on the male and female animals.