Methyl L-threoninate

Endpoint summary

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

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

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

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

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

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

Preliminary study:

NA

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

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.

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.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other:

Remarks:

Further information on read across to L-TEE using the analogue approach can be found in the data matrix table attached as background material and in section 13.

Justification for type of information:

Data on target substance is not available. Thus, read-across has been applied using data from the source substance L-Threonine Ethyl Ester (L-TEE). See further read-across justification in attached background material and in section 13.

Reason / purpose for cross-reference:

read-across source

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

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.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

No data on acute oral toxicity is available on L-Threonine Methylester (L-TME). Data on the read-across substance L-Threonine Ethylester (L-TEE) is available. 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 423. The acute oral median lethal dose (LD50) of L-TEE was estimated to be greater than 2000 mg/kg bw.

As L-TME and L-TEE are small ester molecules, they may be expected to be easily hydrolysed by esterases in the bod, therefrore 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, using human data of 300 mg methanol/kg bw as minimum lethal dose, 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.

Executive summary:

No data on acute oral toxicity is available on L-Threonine Methylester (L-TME). Data on the read-across substance L-Threonine Ethylester (L-TEE) is available. 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 423. The acute oral median lethal dose (LD50) of L-TEE was estimated to be greater than 2000 mg/kg bw.

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, using human data of 300 mg methanol/kg bw as minimum lethal dose, 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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

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. The acute oral median lethal dose (LD50) of L-TEE was estimated to be greater than 2000 mg/kg bw.

L-TME holds the same structure as L-TEE except that L-TME contains a methyl alkyl-side group to the ester bond and L-TEE an ethyl alkyl-side group. The toxicokinetic profile of L-TME and L-TEE is different in terms of the alcohol part (methanol and ethanol) where methanol is considered to be more toxic than ethanol. No interaction of toxicological relevance between L-threonine and the alcohol parts is expected. Read-cross can be made to L-TEE for the L-threonine part of the substance. This will be the same for both esters. The oral toxicity of L-TME is therefore characterised by the toxicity of methanol. 

Due to the structural similarity to L-TEE (the L-Threonine part) and the differences in toxicokinetic properties (methanol and ethanol), the acute oral toxicity of L-TME is described by the toxicity of methanol. Based on the human toxicity profile of methanol, the corresponding oral lethal dose of L-TME assuming 100% hydrolysis to methanol and L-threonine is 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.

Justification for selection of acute toxicity – oral endpoint

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.

L-TME holds the same structure as L-TEE except that L-TME contains a methyl alkyl-side group to the ester bond and L-TEE an ethyl alkyl-side group. The toxicokinetic profile of L-TME and L-TEE is different in terms of the alcohol part (methanol and ethanol) where methanol is considered to be more toxic than ethanol. No interaction of toxicological relevance between L-threonine and the alcohol parts is expected. Read-cross can be made to L-TEE for the L-threonine part of the substance. This will be the same for both esters. The oral toxicity of L-TME is therefore characterised by the toxicity of methanol. 

Due to the structural similarity to L-TEE (the L-Threonine part) and the differences in toxicokinetic properties (methanol and ethanol), the acute oral toxicity of L-TME is described by the toxicity of methanol. Based on the human toxicity profile of methanol, the corresponding oral lethal dose of L-TME assuming 100% hydrolysis to methanol and L-threonine is 1250 mg/kg bw. Hence, according to CLP, L-TME is classified in accordance to toxicity category 4.

Justification for classification or non-classification

Due to the structural similarity to L-TEE (the L-Threonine part) and the differences in toxicokinetic properties (methanol and ethanol), the acute oral toxicity of L-TME is described by the toxicity of methanol. Based on the human toxicity profile of methanol, the corresponding oral lethal dose of L-TME assuming 100% hydrolysis to methanol and L-threonine is 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.