Registration Dossier
Registration Dossier
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EC number: 433-730-7 | CAS number: 23926-51-4 L-THREONINETHYLESTER
Endpoint summary
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
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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