Registration Dossier

Administrative data

Description of key information

L-Glutamine is not be considered to have irritating or corrosive properties to human skin or eye nor to the respiratory system.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1990-03-28 to 1990-04-10
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP guideline study, used for read-across
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
other: White russian (Albino)
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: ASTA Pharma AG, Bielefeld, Germany
- Age at study initiation: 9 - 10 months
- Weight at study initiation: 2.30 - 2.54 kg
- Caging: Stainless steel cages with grating floor, type ASTA
- Diet (e.g. ad libitum): ca,. 120 g /day per animal Standard Diet ssniff K, "Special diet for rabbits", supplied by ssniff Spezialfutter GmbH
- Water (e.g. ad libitum): ad libitum
- Acclimation period: one day acclimatisation period before study begin

ENVIRONMENTAL CONDITIONS
- according to guideline



Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
water
Remarks:
0.5 g of the test substance were moistened with 1.6 ml of demineralized water
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g

VEHICLE
- Amount(s) applied (volume or weight with unit): 1.6 ml
- Purity: demineralized water
Duration of treatment / exposure:
4 h (occlusive patch)
Observation period:
3 d (p. appl.)
Number of animals:
3 males
Details on study design:
TEST SITE
- Area of exposure: ca. 6.25 cm²
- % coverage: entire area of exposure
- Type of wrap (if used): The site of application was covered with a linen cloth which adhered to a synthetic film glue. A bandage (width 8 cm) wrapped several times around the trunk of the animal provided a complete occlusion.
REMOVAL OF TEST SUBSTANCE
- Washing (if done): Remaining Test material was gently washed off as far as posssible.
- Time after start of exposure: 4 h

SCORING SYSTEM:
Irritation index (Draize grade) for
- erythema and eschar
- edema
Primary irritation index modified according to Gilman et al, 1983
Irritation parameter:
erythema score
Basis:
mean
Remarks:
(All individual animals showed score "0".)
Time point:
other: 1 h
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
mean
Remarks:
(All individual animals showed score "0".)
Time point:
other: 24 h
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
mean
Remarks:
(All individual animals showed score "0".)
Time point:
other: 48 h
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
mean
Remarks:
(All individual animals showed score "0".)
Time point:
other: 72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
mean
Remarks:
(All individual animals showed score "0".)
Time point:
other: 1 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
mean
Remarks:
(All individual animals showed score "0".)
Time point:
other: 24 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
mean
Remarks:
(All individual animals showed score "0".)
Time point:
other: 48 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
mean
Remarks:
(All individual animals showed score "0".)
Time point:
other: 72 h
Score:
0
Max. score:
4
Irritation parameter:
primary dermal irritation index (PDII)
Remarks:
modified according to Gilman et al, 1983
Basis:
mean
Remarks:
(Mean value from 12 individual values of 3 animals at 4 observation times.)
Time point:
other: 1 - 72 h
Score:
0
Max. score:
8
Other effects:
Systemic toxic effects did not occur after dermal application of the test substance
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: OECD GHS
Conclusions:
L-Alanyl-L-glutamine was tested on rabbits for skin irritation / skin corrosion properties. The primary irritation index was 0.0. The substance was non-irritant to rabbit skin following a single four-hour application.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1990-03-28 to 1990-04-10
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP guideline study, used for read-across
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
GLP compliance:
yes
Species:
rabbit
Strain:
other: White russian (Albino)
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: ASTA Pharma AG, Bielefeld, Germany
- Age at study initiation: males: 9 months; female: 9 months
- Weight at study initiation: males: 2.63 and 2.89 kg; female: 2.90 kg
- Caging: Stainless steel cages with grating floor, type ASTA
- Diet (e.g. ad libitum): ca. 120 g /day per animal Standard Diet ssniff K, "Special diet for rabbits", supplied by ssniff Spezialfutter GmbH
- Water (e.g. ad libitum): ad libitum
- Acclimation period: The animals were kept one day under test conditions before application of the product.

ENVIRONMENTAL CONDITIONS
- according to guideline
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
0.023 g
Duration of treatment / exposure:
Substance was not actively removed from the eye
Observation period (in vivo):
3 days
Number of animals or in vitro replicates:
3; 2 males and 1 female
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): no rinsing
- Time after start of exposure: not actively removed

SCORING SYSTEM:
Draize

TOOL USED TO ASSESS SCORE: hand-slit lamp
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24 hours; 48 hours; 72 hours
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24 hours; 48 hours; 72 hours
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24 hours; 48 hours; 72 hours
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 24 hours
Remarks on result:
other: Max. scores: (a) Redness: 3. (b) Chemosis: 4. (c) Discharge: 3. Total maxiumum = Σ(a+b+c)x2:12
Irritant / corrosive response data:
Conjunctivae reactions were limited to slight redness at 2 animals after 1 hour observation.
Other effects:
No other effects detected
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: OECD GHS
Conclusions:
L-Alanyl-L-glutamine was tested on three rabbits for eye irritation. The primary irritation index was 0.3. The substance was classified as non-irritant on the eye of the rabbit following a single application.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

Common Read-Across for Skin Irritation/Corrosion and Eye Irritation/Corrosion

 Read-across was performed from studies for a dipeptide containing L-glutamine (L-alanyl-L-glutamine).

  

Skin

 L-alanyl-L-glutamine was tested for skin irritation / skin corrosion. The substance was non-irritant to rabbit skin following a single four-hour application. The results of a supporting study also indicate that L-glutamine is not irritating, the test substance even reduces skin irritation caused by sodium caprate.

The results provide weight of evidence that L-glutamine is non irritant.

The dipeptide (L-alanyl-L-glutamine) does not exhibit a SAR (structural alert or set of fragments) for skin irritation / corrosion (BfR rule base: ECETOC, 1995; Gerner at al., 2004; Walker, 2004; RVIM, 2005) to induce one of the different types of irritant contact dermatitis (ICD). The occurrence of structural analogues that exhibit corrosion (or irritation) potential can be used to predict the effect in the substance of interest and derogate from further assessment, as indicated in the OECD testing strategy for skin irritation/corrosion (OECD, 2001). Negative data from structural analogues may also be used to make predictions in certain cases, provided that there are no other substructures in the substance that are thought likely to cause the effect (ECHA, 2008). This is the case for L-glutamine to read-across. The result of the dipeptide study also indicates that the L-alanine amino acid residue is not irritant to the skin, this is applicable also to the L-glutamine amino acid residue.

  

ECETOC (1995): Technical report No. 66 Skin irritation and corrosion: Reference chemicals data bank.Brussels, 1995

Gerner I., Schlegel K., Walker J.D., Hulzebos, E. (2004).Use of physico-chemical property limits to develop rules for identifying chemical substances with no skin irritation or corrosion potential. QSAR and Combinatorial Science 23, 726-733.

ECHA (2008): Guidance on information requirements and chemical safety assessment Chapter R.7a: Endpoint specific guidance.

OECD (2001) OECD Attachment to the Test Guideline 404: A Sequential Testing Strategy for Skin Irritation and Corrosion. OECD, Paris, France.

RIVM (2005): Hulzebos, E., Sijm, D., Traas, T., Posthumus, R., Maslankiewicz, L. (2005) Validity and validation of expert (Q)SAR systems. SAR and QSAR in Environmental Research 16, 385-401.

Walker, J.D., Gerner, I., Hulzebos, E., Schlegel, K. (2004) (Q)SARs for Predicting Skin Irritation and Corrosion: Mechanisms, Transparency and Applicability of Predictions.QSAR & Combinatorial Science 23, 721-725.

Eye

 L-alanyl-L-glutamine was tested for eye irritation / eye corrosion. The substance was non-irritant to rabbit eye following a single application. The substance is not to be classified as an eye irritant according to the criteria of the CLP-regulation (Regulation 1272/2008).

The results provide weight of evidence that L-glutamine is non irritant.

The result of the dipeptide study also indicates that the L-alanine amino acid residue is not irritant to the eye, this is applicable also to the L-glutamine amino acid residue.

Respiratory System

There are no data available which indicate that L-glutamine is irritant to the respiratory system.

 

Justification for selection of skin irritation / corrosion endpoint:

Key study

Justification for selection of eye irritation endpoint:

Key study

Justification for classification or non-classification

Read-across provides substantial weight of evidence that L-glutamine does not show irritating or corrosive properties both to skin and eye.