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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
NA
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Exposure based waiving (Adaption to column 2 - Annex XI section 3 "Substance-Tailored Exposure-Driven Testing"):

L-TEE is only used in the production of a pharmaceutical product under conditions with very low potential human exposure (worker). No exposure to the general population as L-TEE is only used in industrial settings. A full description of the exposure can be found in the attached CSR (section 13). In the CSR it is concluded that for all industrial uses, very low exposure levels are identified and RCRs well below 0.02 compared to a DNEL of 23 mg/m3 or 3.3 mg/kg bw/day . Any combination of uses will result in an RCR below 0.2. Workers will not be exposed at any critical level.

Further toxicological aspects:

L-TEE is highly water soluble, hydrolysis products is L-threonine (CAS no 72-19-5) and ethanol (CAS no 64-17-5). The following toxicological data has been extracted from the REACH registration dossiers for ethanol and L-threonine: Ethanol: In a two-generation study, ethanol in drinking water at concentrations up to 15% (equivalent to 20.7 g/kg/day) had no demonstrable effect on fertility. In a inhalational developmental toxicity study using 10,000, 16,000 or 20,000 ppm (equivalent to 17, 29 and 28 g/kg bw), NOAEL (maternal toxicity) of 16,000ppm (30,400 mg/m3) and NOAEL (teratogenicity) of 20,000ppm (38,000mg/m3) was derived. Based on these data, no reproductive and developmental toxicity has been identified. These NOAEL values on reproduction are many orders of magnitude higher than the DNEL currently used for L-TEE. L-threonine: the amino-acid L-threonine is essential for humans as a macronutrient and a normal component of proteins. Normal human exposure is through food and the use of L-threonine as flavouring agents was evaluated not to raise any safety concerns (WHO, 2012, Safety evaluation of certain food additives).

Overall, L-TEE is an ester formed by L-threonine and ethanol, both of which are substances that are readily metabolized in the body. A high degree of endogenous hydrolysation into these substances is expected due to the activity of normally occurring esterases. However, no specific data on the hydrolysation rates are available. In terms of reproductive and developmental toxicity of ethanol and L-threonine, no concern is indicated especially taking into account the very lowexposure to L-TEE.

Therefore, based on these arguments no further experimental animal testing for reproductive toxicity for L-TEE is considered scientifically justified.


Justification for selection of Effect on fertility via oral route:
Exposure based waiving as L-TEE is handled and used in a closed system with neglible human exposure.

Justification for selection of Effect on fertility via inhalation route:
Exposure based waiving as L-TEE is handled and used in a closed system with neglible human exposure.

Justification for selection of Effect on fertility via dermal route:
Exposure based waiving as L-TEE is handled and used in a closed system with neglible human exposure.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Exposure based waiving (Adaption to column 2 - Annex XI section 3 "Substance-Tailored Exposure-Driven Testing"):

L-TEE is only used in the production of a pharmaceutical product under conditions with very low potential human exposure (worker). No exposure to the general population as L-TEE is only used in industrial settings. A full description of the exposure can be found in the attached CSR (section 13). In the CSR it is concluded that for all industrial uses, very low exposure levels are identified and RCRs well below 0.02 compared to a DNEL of 23 mg/m3 or 3.3 mg/kg bw/day . Any combination of uses will result in an RCR below 0.2. Workers will not be exposed at any critical level.

Further toxicological aspects:

L-TEE is highly water soluble, hydrolysis products is L-threonine (CAS no 72-19-5) and ethanol (CAS no 64-17-5). The following toxicological data has been extracted from the REACH registration dossiers for ethanol and L-threonine: Ethanol: In a two-generation study, ethanol in drinking water at concentrations up to 15% (equivalent to 20.7 g/kg/day) had no demonstrable effect on fertility. In a inhalational developmental toxicity study using 10,000, 16,000 or 20,000 ppm (equivalent to 17, 29 and 28 g/kg bw), NOAEL (maternal toxicity) of 16,000ppm (30,400 mg/m3) and NOAEL (teratogenicity) of 20,000ppm (38,000 mg/m3) was derived. Based on these data, no reproductive and developmental toxicity has been identified. These NOAEL values on reproduction are many orders of magnitude higher than the DNEL currently used for L-TEE. L-threonine: the amino-acid L-threonine is essential for humans as a macronutrient and a normal component of proteins. Normal human exposure is through food and the use of L-threonine as flavouring agents was evaluated not to raise any safety concerns (WHO, 2012, Safety evaluation of certain food additives).

Overall, L-TEE is an ester formed by L-threonine and ethanol, both of which are substances that are readily metabolized in the body. A high degree of endogenous hydrolysation into these substances is expected due to the activity of normally occurring esterases. However, no specific data on the hydrolysation rates are available. In terms of reproductive and developmental toxicity of ethanol and L-threonine, no concern is indicated especially taking into account the very lowexposure to L-TEE.

Therefore, based on these arguments no further experimental animal testing for reproductive toxicity for L-TEE is considered scientifically justified.


Justification for selection of Effect on developmental toxicity: via oral route:
Exposure based waiving as L-TEE is handled and used in a closed system with neglible human exposure

Justification for selection of Effect on developmental toxicity: via inhalation route:
Exposure based waiving as L-TEE is handled and used in a closed system with neglible human exposure

Justification for selection of Effect on developmental toxicity: via dermal route:
Exposure based waiving as L-TEE is handled and used in a closed system with neglible human exposure

Toxicity to reproduction: other studies

Additional information

NA

Justification for classification or non-classification

Additional information