Ethyl L-threoninate

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

October 5, 2007 - October 19, 2007

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

Minor deviations in temperature, humidity and oxygen concentration were observed during the study period but these deviations did not affect the integrity of the study.

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:

2008

Report date:

2008

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Deviations:

yes

Remarks:

temperature, humidity and oxygen concentration

Test guideline 2

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

yes

Remarks:

temperature, humidity and oxygen concentration

Principles of method if other than guideline:

NA

GLP compliance:

yes (incl. QA statement)

Test type:

fixed concentration procedure

Limit test:

yes

Test material

Test material information

Constituent 1

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Name of test material (as cited in study report): L-TEE
- Analytical purity: 99.6%
- Purity test date: no data
- Lot/batch No.: 0706H013
- Expiration date of the lot/batch: 1 February 2009
- Stability under test conditions: stored at room temperature in sealed container
- Storage condition of test material: frozen

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch number of test material: 0706H013
- Expiration date of the lot/batch: 1 February 2009
- Purity test date: 2 April 2007


STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: 10 - 30°C
- Stability under test conditions: stable under the chosen method of aerosol generation


TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: test article was prepared as a solution in purified (double distilled) water.
- Final dilution of a dissolved solid, stock liquid or gel: 400 mg/mL

FORM AS APPLIED IN THE TEST (if different from that of starting material)

INFORMATION ON NANOMATERIALS
- Particle size & distribution: Mass Median Aerodynamic Diameter 2.25 µm

Test animals

Species:

rat

Strain:

Wistar

Remarks:

HsdRccHan: WIST

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan UK Limited, Bicester
- Age at study initiation: 8 to 10 weeks
- Weight at study initiation: mean for males 208g, mean for females 171g.
- Fasting period before study: while retained for exposure, animals did not have access to food and water
- Housing: single room
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 10 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.3 to 19.5°C
- Humidity (%): 70.1 to 75.0 %
- Air changes (per hr): 12 air changes/hour
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: September 25, 2007 to October 19, 2007.

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: The test article was prepared as a solution in purified (double-destilled) water as it was not possible to produce a respirable aerosol from the solid test article.

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: flow-through exposure chamber
- Exposure chamber volume: 40L
- Method of holding animals in test chamber: Inhalation chambers
- Source and rate of air: no data
- Method of conditioning air: no data
- System of generating particulates/aerosols: Hospital Clinical nebuliser
- Method of particle size determination: gravimetrically
- Treatment of exhaust air: no data
- Temperature, humidity, pressure in air chamber: 18.9°C, 72.4 %, 20.5 % (v/v)

TEST ATMOSPHERE
- Brief description of analytical method used: the aerosol was sampled approx. twice hourly during the animal exposure.
- Samples taken from breathing zone: yes

VEHICLE
- Composition of vehicle (if applicable): purified (double-distilled) water
- Concentration of test material in vehicle (if applicable): 400 mg/mL
- Justification of choice of vehicle: solubility


TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: determined gravimetrically, and sampled using a Marple Andersen 298 Cascade Impactor
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 2.32µm / 2.41

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration: NA

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

The aerosol concentration ranged between 5.42 and 6.82mg/L. The mean concentration was 6.16mg/L.

No. of animals per sex per dose:

5 males and 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations daily, weighing on Day 1, 2, 3, 8 and 15.
- Necropsy of survivors performed: yes (all animals)
- Other examinations performed: clinical signs, body weight,necropsy

Statistics:

Report generation and statistal analysis: Costar/Office 97

Results and discussion

Preliminary study:

None

Effect levels

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5 mg/L air

Exp. duration:

4 h

Mortality:

No animals died

Clinical signs:

other: Clinical signs of reaction to treatment were confined to wet fur, staining of the snout and unkempt appearance. These signs were present during exposure and lasted up to Day 3. Chromodacryorrhoea was also noted in two males during the exposure.

Body weight:

All rats achieved body weight gains during the first and second weeks of the study.

Gross pathology:

No macroscopic changes were observed at necropsy.

Other findings:

- Organ weights: not performed
- Histopathology: not performed
- Potential target organs: None

Any other information on results incl. tables

None

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The acute inhalation toxicity of L-TEE was assessed in rats using a single exposure via inhalation (nose only) in an exposure chamber of approximate volume 40L. The study was performed in accordance with testing guidelines EC (method B2) and OECD (403).

The acute median lethal dose level (LC50) was found to exceed 5 mg/L.

Executive summary:

L-TEE formulation was administered as a single exposure via inhalation (nose only) in an exposure chamber of approximate volume 40 L. A limit test was performed using five males and five females exposed for four hours to an exposure concentration of approximately 5.04mg/L. All animals were killed on Day 15 and subsequently underwent a full necropsy.

No animal died. Clinical signs of reaction to treatment were confined to wet fur, staining of the snout and unkempt appearance. These signs were present during exposure and lasted up to Day 3. Chromodacryorrhoea was also noted in two males during the exposure.

Recovery, as judged by external appearance and behaviour, was complete by Day 4. All rats achieved body weight gains during the first and second weeks of the study. No macroscopic changes were observed at necropsy.

The acute median lethal dose level (LC50) was found to exceed 5 mg/L.