4-isopropyl-m-cresol

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From September 24 to October 23, 2003

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study conducted according to OECD test Guideline No. 403 without any deviation.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2004

Report date:

2004

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

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes (incl. QA statement)

Remarks:

UK GLP Compliance Programme (inspected on December 02, 2002/ signed on February 13, 2003)

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

4-isopropyl-m-cresol

EC Number:

221-761-7

EC Name:

4-isopropyl-m-cresol

Cas Number:

3228-02-2

Molecular formula:

C10H14O

IUPAC Name:

4-isopropyl-m-cresol

Test material form:

other: solid

Details on test material:

- Name of test material (as cited in study report): Biosol
- Physical state: White crystalline Solid
- Storage condition of test material: Room temperature in the dark

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent.
- Age at study initiation: Approximately 8-12 weeks
- Weight at study initiation: 200-350 g
- Housing: Animals were housed in groups of five per sex in solid-floor polypropylene cages with stainless steel lids, furnished with softwood flakes and provided with environmental enrichment items: wooden chew blocks and cardboard "fun tunnels"
- Diet: Food (EU Rodent Diet 5LF2, IPS Limited, Wellingborough, Northants, UK), ad libitum
- Water: Drinking water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 21 ± 2°C
- Humidity: 55 ± 15%
- Air changes: 15 changes/hour
- Photoperiod: 12 hours dark / 12 hours light

IN-LIFE DATES: From September 24 to October 23, 2003

Administration / exposure

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

other: compressed air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Cylindrical exposure chamber; dynamic (continuous flow)
- Exposure chamber volume: Approximately 30 L (dimensions: 28 cm diameter x 50 cm high)
- Method of holding animals in test chamber: Each rat was individually held in a tapered, polycarbonate restraining tube fitted onto a single tier of the exposure chamber and sealed by rubber 'O' ring. Only the nose of each animal was exposed to the test atmosphere.
- Source and rate of air: Compressed air was supplied by an oil free compressor; chamber flow rate was maintained at 40 L/min providing 80 air changes per hour
- Method of conditioning air: Air was passed through a water trap and respiratory quality filters before it was introduced into the SAG 410.
- Atmosphere generation: A dust atmosphere was produced from the test material using a SAG 410 Solid Aerosol Generator (TOPAS GmbH, Dresden, Germany) located adjacent to the exposure chamber. The SAG 410 was connected to a metered compressed air supply.
- Method of particle size determination: The particle size of generated atmosphere inside the exposure chamber was determined three times during the exposure period using a Marple Personal Cascade Impactor (Schaefer Instruments Ltd, Oxon., UK).
- Temperature and relative humidity inside the exposure chamber was measured by an electronic thermometer/humidity meter located in a vacant part in the animal's breathing zone of the chamber and recorded every thirty minutes throughout the 4 hours exposure period.
- Exposure chamber oxygen concentration was measured by an electronic oxygen analyser (Servomex (UK) Ltd, Crowborough, East Sussex) located in a sampling part in the animal's breathing zone during each exposure period.

TEST ATMOSPHERE
- Brief description of analytical method used:
Gravimetric method: Air in the breathing zone was drawn through glass fibre filters (Gelman type A/E 25 mm) and the employed filters weighed before and after sampling. The difference in the two weights, divided by the volume of atmosphere sampled, gave the actual chamber concentration.
- Samples taken from breathing zone: Yes

TEST ATMOSPHERE
- See the table 7.2.2/1 and 7.2.2/1

- Prior to the start of the study, test material atmospheres were generated within the exposure chamber. During this characterisation period, extensive work was performed in an attempt to achieve a sustainable atmosphere at maximum concentration. This included alternative grinding techniques and varying the generation system. No significant improvement could be made to the achieved atmosphere concentrations or particle size distributions and therefore, the concentration achieved is considered the maximum attainable.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

Gravimetric method

Duration of exposure:

4 h

Concentrations:

Nominal concentration: 77.0 mg/L
Mean maximum attainable atmosphere concentration: 1.41 mg/L

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: All animals were observed for clinical signs at hourly intervals during exposure, immediately on removal from the restraining tubes at the end of exposure, one hour after termination of exposure and subsequently once daily for fourteen days. All animals were observed for mortality throughout the study period.
- Frequency of weighing: Individual bodyweights were recorded prior to treatment on the day of exposure and on Days 7 and 14.
- Necropsy of survivors performed: Yes, at the end of 14 days observation period the animals were killed by intravenous overdose of sodium pentobarbitone and subjected to complete external and internal examination for macroscopic abnormalities. The respiratory tract was examined macroscopically for signs of irritancy or local toxicity.

Statistics:

None

Results and discussion

Preliminary study:

Not applicable

Effect levels

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 1.41 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: no mortality was observed

Mortality:

No mortality was observed throughout the study period

Clinical signs:

other: - Signs of hunched posture, pilo-erection and red/brown staining around the snout and/or eyes are commonly seen in animals for short periods on removal from the chamber following 4-hour inhalation studies. Wet fur is commonly recorded both during and for

Body weight:

- Normal bodyweight gain was observed during the study.
- Several females showed reduction in body weight gain or a slight body weight loss during Week 1 and/or 2 but such variations are not uncommon in female rats of this strain and age are considered not to be significant.

Gross pathology:

No macroscopic abnormalities were detected at necropsy.

Other findings:

None

Any other information on results incl. tables

None

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The combined inhalational LC50 was greater than 1.41 mg/L (mean maximum attainable atmosphere concentration). Under the test conditions, test item should not be classified according to the criteria of the Annex VI of the Directive 67/548/EEC and the CLP Regulation (EC) N° (1272-2008).

Executive summary:

In an acute inhalational toxicity study performed in accordance with GLP and OECD guideline 403, groups (5/sex) of Sprague Dawley Crl:CD® (SD) IGS BR rats were exposed to a dust atmosphere of Biosol at the mean maximum attainable atmosphere concentration of 1.41 mg/L air (nominal concentration: 77.0 mg/L) for 4 hours. Animals were then observed for mortality, clinical signs and bodyweights for 14 days and necropsy was performed in all animals for macroscopical examination.

 

Common abnormalities noted during the study included increased respiratory rate, hunched posture and pilo-erection and there were isolated instance of red/brown staining to the eyes and/or snout. All animals recovered quickly to appear normal from Day 1 or 2 post-exposure. Normal bodyweight gain was observed during the study. Several females showed reduction in body weight gain or a slight body weight loss during Week 1 and/or 2 but such variations are not uncommon in female rats of this strain and age are considered not to be significant. No macroscopic abnormalities were detected at necropsy.

The combined inhalational LC50 was greater than 1.41 mg/L (mean maximum attainable atmosphere concentration).

 

Under the test conditions, test item should not be classified according to the criteria of the Annex VI of the Directive 67/548/EEC and the CLP Regulation (EC) N° (1272-2008).