Levoglutamide

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

L-Glutamine did not show effects on the reproductive organs in general repeated dose toxicity studies. Furthermore, a QSAR predicts no toxicity to reproduction.

Moreover, L-glutamine is an amino acid that is required for normal functioning of humans. The substance is of low toxicological activity and subject to homeostasis. Therefore, reprotoxic effects are not expected for L-glutamine and no test is required for this substance.

There is sufficient weight of evidence for the absence of reprotoxic effects. A screening for reproductive toxicity (REACH Annex VIII No. 8.7.1) as well as any study on reproductive toxicity as REACH Annex IX no. 8.7 are not to be conducted in accordance with REACH Annex XI no. 1.2. and for reasons of animal welfare: "Where sufficient weight of evidence for the presence or absence of a particular dangerous property is available, further testing on vertebrate animals for this property shall be omitted..."

Link to relevant study records

Reference

Reference 1

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

1. SOFTWARE: QSAR Toolbox 4.5
2. MODEL (incl. version number): Androgen Receptor Antagonism (Human in vitro) - Danish QSAR DB battery model (v.1.0)
3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL: N[C@H](CCC(N)=O)C(O)=O
4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: AR antagonism; Androgen Receptor Binding

5. APPLICABILITY DOMAIN: The target chemical FALLS within the applicability domain, please see report attached

Principles of method if other than guideline:

SAR/QSAR prediction: Calculation based on QSAR Toolbox 4.5. model: Androgen Receptor Antagonism (Human in vitro) - Danish QSAR DB battery model (v.1.0)

GLP compliance:

no

Details on study design:

Data gap filling method: Read-across analysis, Human Health Hazards -> Toxicity to
Reproduction -> AR antagonism -> Homo sapiens

Remarks on result:

other: Predicted value: Negative

Remarks on result:

other: Predicted value: Negative

Reproductive effects observed:

no

Conclusions:

QSAR predicts that toxicity to reproduction is negative for L-Glutamine.

Reference 2

Endpoint:

screening for reproductive / developmental toxicity

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
L-Glutamine did not show effects on the reproductive organs in general repeated dose toxicity studies. Furthermore, a QSAR for the endpoint reproductive toxicity predicts no toxicity to reproduction.

Moreover, L-glutamine is an amino acid that is required for normal functioning of humans. The substance is of low toxicological activity and subject to homeostasis.

A significant amount of L-glutamine is usually taken up via the food. In usual diet, most amino acids are supplied as constituents of protein and not as free amino acid. Protein intake clearly modifies plasma amino acid levels. However, amino acid concentrations are subject to homeostasis and the plasma concentrations vary within fixed limits and are tightly regulated.

Exposure with L-glutamine from uses which are covered by this registration would only marginally increase the total daily L-glutamine dose which is taken up via the food. Even if the plasma amino acid concentration would increase/vary by any use such fluctuations are physiological and subject to homeostasis.

Several repeated dose toxicity studies consistently indicate the very low toxicity of L-glutamine. Even in very high doses no toxicity is observed and no adverse effects were reported for the reproductive organs. Therefore, reprotoxic effects are not expected for L-glutamine and no test is required for this substance.

There is sufficient weight of evidence for the absence of reprotoxic effects. A screening for reproductive toxicity (REACH Annex VIII No. 8.7.1) as well as any study on reproductive toxicity as REACH Annex IX no. 8.7 are not to be conducted in accordance with REACH Annex XI no. 1.2. and for reasons of animal welfare: "Where sufficient weight of evidence for the presence or absence of a particular dangerous property is available, further testing on vertebrate animals for this property shall be omitted..."

Reproductive effects observed:

not specified

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

There are no studies for reproductive toxicity/developmental toxicity of L-glutamine accessible to the registrant.

L-Glutamine did not show effects on the reproductive organs in general repeated dose toxicity studies. Furthermore, a QSAR predicts no toxicity to reproduction.

Moreover, L-glutamine is an amino acid that is required for normal functioning of humans. The substance is of low toxicological activity and subject to homeostasis. Therefore, reprotoxic effects are not expected for L-glutamine and no test is required for this substance.

A significant amount of L-glutamine is usually taken up via the food. In usual diet, most amino acids are supplied as constituents of protein and not as free amino acid. Protein intake clearly modifies plasma amino acid levels. However, amino acid concentrations are subject to homeostasis and the plasma concentrations vary within fixed limits and are tightly regulated.

Exposure with L-glutamine from uses which are covered by this registration would only marginally increase the total daily L-glutamine dose which is taken up via the food. Even if the plasma amino acid concentration would increase/vary by any use such fluctuations are physiological and subject to homeostasis.

Several repeated dose toxicity studies consistently indicate the very low toxicity of L-glutamine. Even in very high doses no toxicity is observed and no adverse effects were reported for the reproductive organs.

Therefore it is highly unlikely that L-glutamine taken up via any use covered by this registration would result in systemic effects including effects on unborn life.

Short description of key information:

It is not expected that L-glutamine does affect fertility. No test is required for this substance.

Effects on developmental toxicity

Description of key information

There are no studies for reproductive toxicity/developmental toxicity of L-glutamine accessible to the registrant.

L-Glutamine did not show effects on the reproductive organs in general repeated dose toxicity studies. Furthermore, a QSAR predicts no toxicity to reproduction.

Moreover, L-glutamine is an amino acid that is required for normal functioning of humans. The substance is of low toxicological activity and subject to homeostasis. Therefore, reprotoxic effects are not expected for L-glutamine and no test is required for this substance.

A significant amount of L-glutamine is usually taken up via the food. In usual diet, most amino acids are supplied as constituents of protein and not as free amino acid. Protein intake clearly modifies plasma amino acid levels. However, amino acid concentrations are subject to homeostasis and the plasma concentrations vary within fixed limits and are tightly regulated.

Exposure with L-glutamine from uses which are covered by this registration would only marginally increase the total daily L-glutamine dose which is taken up via the food. Even if the plasma amino acid concentration would increase/vary by any use such fluctuations are physiological and subject to homeostasis.

Several repeated dose toxicity studies consistently indicate the very low toxicity of L-glutamine. Even in very high doses no toxicity is observed and no adverse effects were reported for the reproductive organs.

Therefore it is highly unlikely that L-glutamine taken up via any use covered by this registration would result in systemic effects including effects on unborn life.

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

Regarding reproductive toxicity/developmental toxicity no study reports for L-glutamine are accessible to the registrant. L-Glutamine did not show effects on the reproductive organs in general repeated dose toxicity studies. Furthermore, a QSAR predicts no toxicity to reproduction. A significant amount of L-glutamine is usually taken up via the food. In usual diet, most amino acids are supplied as constituents of protein and not as free amino acid. Protein intake clearly modifies plasma amino acid levels. However, amino acid concentrations are subject to homeostasis and the plasma concentrations vary within fixed limits and are tightly regulated. Exposure with L-glutamine from uses which are covered by this registration would only marginally increase the total daily L-glutamine dose which is taken up via the food. Even if the

plasma amino acid concentration would increase/vary by any use such fluctuations are physiological and subject to homeostasis. Therefore it is highly unlikely that L-glutamine taken up via any use covered by this registration would result in systemic effects including effects on unborn life.

There is sufficient weight of evidence for the absence of developmental toxicity / teratogenicity. Any study on developmental toxicity / teratogenicity as REACH Annex IX no. 8.7 are not to be conducted in accordance with REACH Annex XI no. 1.2. and for reasons of animal welfare: "Where sufficient weight of evidence for the presence or absence of a particular dangerous property is available, further testing on vertebrate animals for this property shall be omitted..."

Justification for classification or non-classification

There is no indication that L-glutamine causes toxicity to reproduction. Thus, classification as to reproductive toxicity according to EU-GHS is not required.