Methyl L-threoninate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2000

Report date:

2000

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

Principles of method if other than guideline:

NA

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

L-TEE

IUPAC Name:

L-TEE

Test material form:

solid: particulate/powder

Details on test material:

- Name of test material (as cited in study report): Threonineethylester
- Analytical purity: 97%
- Purity test date: No data
- Lot/batch No.: 142-576-6
- Expiration date of the lot/batch: No data
- Stability under test conditions: Considered to be stable during testing
- Storage condition of test material: Frozen

Test animals

Species:

rat

Strain:

other: Crl:Wl(Glx/BRL/han)BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate
- Age at study initiation: 9 to 11 weeks old
- Weight at study initiation: 285-319g (males), 178-194g (females)
- Fasting period before study: overnight prior to dosing
- Housing: suspended stainless steel mesh cages
- Diet (e.g. ad libitum): ad libitum, except overnight prior to dosing and three hours after dosing
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 or 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25°C
- Humidity (%): 40-70 % RH
- Air changes (per hr): 12 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours daily with flurorescent strip-lights

IN-LIFE DATES: From 11 April or 9 May 200 to 30 May 2000

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: Purified water from on site Elgastat purifier.

Details on oral exposure:

VEHICLE
- Concentration in vehicle: Dispersed in purified water to reach 10/20 mL/kg bw
- Justification for choice of vehicle: solubility

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg (males) and 20 mL/kg (females)

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Dose selection followed the Acute Toxic Class procedure detailed in EC and OECD guidelines.

Doses:

2000 mg/kg

No. of animals per sex per dose:

3 males and 3 females

Control animals:

no

Details on study design:

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

Statistics:

NA

Results and discussion

Preliminary study:

NA

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

No mortality was observed

Clinical signs:

other: No clinical signs was observed

Gross pathology:

No macroscopic changes were observed for animals killed on Day 15.

Other findings:

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

Any other information on results incl. tables

At a first sight and based on read across to acute oral toxicity data on L-TEE, L-TME should not be considered to be an acute oral toxicant. However, as L-TME and L-TEE are small ester molecules, they may be expected to be easily hydrolysed by esterases in the body the acute toxicity may as well be determined by the product of hydrolysis. In that respect methanol should be considered much more toxic than ethanol in relation to human exposure.

For methanol toxicity, human data needs to be used, because rats are insensitive to the toxicity of methanol (ref. e.g. ECHA guidance on CLP criteria v4, November 2013, p282). In terms of human experience methanol is known to cause lethal intoxications in humans (mostly via ingestion) in relatively low doses (300-1000 mg/kg bw) (ref. e.g. ECHA guidance on CLP criteria v4, November 2013, p282). Using 300 mg methanol/kg bw as minimum lethal dose, the corresponding theoretical L-TME dose would be:

Mw of L-TME is 133 Dalton of L-threonine is 101 Dalton and methanol is 32 Dalton. Methanol part of L-TME constitutes approx. 24%. The corresponding oral lethal dose of L-TME assuming 100% hydrolysis to methanol and L-threonine would be 1250 mg/kg bw.

Thus from a precautionary view L-TME can according to the CLP-criteria for acute toxicity be classified as acute tox 4.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The acute oral toxicity of L-TEE was assessed in rats following a single administration of L-TEE. The study was performed in compliance with OECD guideline 423 and ECC guideline B1 tris. L-TEE was dispersed in purified water and administered at a dose volume of 10 (male) or 20 mL/kg (female). The acute oral median lethal dose (LD50) of L-TEE was estimated to be greater than 2000 mg/kg bw.

Executive summary:

The acute oral toxicity of L-TEE was assessed in rats following a single administration of L-TEE. The study was performed in compliance with OECD guideline 423 and ECC guideline B1 tris. L-TEE was dispersed in purified water and administered at a dose volume of 10 (male) or 20 mL/kg (female). The acute oral median lethal dose (LD50) of L-TEE was estimated to be greater than 2000 mg/kg bw.