Registration Dossier

Administrative data

Description of key information

A theorical AOP (adverse outcome pathway) approach was considered on the test substance but shows its limits when it comes to complexe substances:

-the key event n°1 being the DPRA (OECD 442C) was not possible taking into account the UVCB composition of the substance.

-the key event n°2 (Keratinosens test (OECD guideline 442D) was performed and was negative.

-the key event n°3 was considered a non-necessary due to the fact that raw materials are not known to be skin sensitizers (see corresponding endpoint study records); the process is a soft extraction at room temperature. It extracts the ethanol soluble constituents which are mainly saccharides, flavonoids bound to saccharides, acids and doesn’t create new potential sensitizer substances. The Keratinosens result confirms this pragmatic approach.

 Those combined information allow us to expect that the substance is not a skin sensitizer.

 

Please see report in 13.2 for more information.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in vitro
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 442D (In Vitro Skin Sensitisation: ARE-Nrf2 Luciferase Test Method)
GLP compliance:
yes (incl. certificate)
Type of study:
activation of keratinocytes
Details on study design:
Test item
The test item was tested at 12 concentrations according to a geometric progression of ratio 2 from 0.2 µg/ml to 400 µg/ml.

Reference item
Negative control: 6 wells of solvent control (1% DMSO in treatment medium) with cells and 1 well of solvent control without cell by culture plate.
Positive control: 5 concentrations of cinnamaldehyde on each culture plate. The concentration varies from 4 to 64 µM according to a geometric progression of ratio 2.

The study was composed of two independent repetitions. For each repetition the test item and the reference items were replicated on three independent plates for the measurement of induction and two plates for the measurement of cytotoxicity. Each repetition was performed on a different day with fresh stock solution.
Key result
Parameter:
other: IC70 (viability)
Remarks:
in µg/ml
Value:
> 400
Vehicle controls validity:
valid
Negative controls validity:
not applicable
Positive controls validity:
valid
Interpretation of results:
GHS criteria not met
Executive summary:

The skin sensitization in vitro was performed according to the OECD 442D guideline.

The test substance wasn't considered as a skin sensitizer.

Endpoint:
skin sensitisation: in vitro
Remarks:
in vitro assessment of the potential modulation of the surface marker expression and morphology of pure mature murine Langerhans cells
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1999
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: data from litterature, no guideline followed. Data used in a weight of evidence strategy.
Qualifier:
no guideline followed
Principles of method if other than guideline:
data from litterature, no guideline followed. Data used in a weight of evidence strategy.
GLP compliance:
no
Type of study:
activation of dendritic cells
Justification for non-LLNA method:
Literature data, used in a weight of evidence approach
The capacity of sensitizers, irritants and neutral chemicals to modulate the surface marker expression and morphology of pure mature murine Langerhans cells in vitro was examined.
Details on study design:
he capacity of sensitizers, irritants and neutral chemicals to modulate the surface marker expression and morphology of pure mature murine Langerhans cells in vitro was examined. Contact with 4 sensitizers (2,4-dinitrobenzenesulfate, 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one, p-phenylenediamine, mercaptobenzo-thiazole) resulted in a rapid, specific, marked fall in 33D1 expression, a murine specific dendritic cell marker. No effect was observed with 2 neutral chemicals (sodium chloride, methyl nicotinate) or 2 irritants (dimethyl sulfoxide, benzalkonium chloride).
Positive control results:
Contact with 4 sensitizers (2,4-dinitrobenzenesulfate, 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one, p-phenylenediamine, mercaptobenzo-thiazole) resulted in a rapid, specific, marked fall in 33D1 expression, a murine specific dendritic cell marker.
Key result
Remarks on result:
no indication of skin sensitisation
Interpretation of results:
GHS criteria not met
Conclusions:
Langerhans cells play a critical role in allergic contact hypersensitivity. In vivo, these cells capture xenobiotics that penetrate the skin and transport them through the lymphatic vessels into regional lymph nodes for presentation to T cells. During this migration step, Langerhans cells become mature dendritic cells according to their phenotype and their high immunostimulatory capacity. In vitro, when isolated from the skin and cultured for 3 days, Langerhans cells undergo similar phenotypic and functional maturation. In this study, the capacity of sensitizers, irritants and neutral chemicals to modulate the surface marker expression and morphology of pure mature murine Langerhans cells in vitro was examined. Contact with 4 sensitizers (2,4-dinitrobenzenesulfate, 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one, p-phenylenediamine, mercaptobenzo-thiazole) resulted in a rapid, specific, marked fall in 33D1 expression, a murine specific dendritic cell marker. No effect was observed with 2 neutral chemicals (sodium chloride, methyl nicotinate) or 2 irritants (dimethyl sulfoxide, benzalkonium chloride). Nevertheless, sodium lauryl sulfate, a very irritant detergent, altered morphology and down-regulated all membrane markers. These preliminary data suggest that in vitro modulation of 33D1 expression by strong sensitizers may be an approach to the development of an in vitro model for the identification of chemicals that have the potential to cause skin sensitization and to distinguish them as far as possible from irritants.
Executive summary:

Herouet et al. studied the sensitization potential of several chemicals (Contact sensitizers decrease 33D1 expression on mature Langerhans cells, 1999) on Langerhans cells which play a critical role in allergic contact hypersensitivity.

No effect was observed with sodium chloride.

Endpoint:
skin sensitisation, other
Remarks:
clinical study
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1994
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: data from litterature, no guideline followed. Data used in a weight of evidence strategy.
Qualifier:
no guideline followed
Principles of method if other than guideline:
data from litterature, no guideline followed. Data used in a weight of evidence strategy.
GLP compliance:
no
Type of study:
patch test
Justification for non-LLNA method:
Literature data, used in a weight of evidence approach.
In order to study the prevalence of allergy to onion, skin prick tests were performed.
Species:
other: human
Strain:
not specified
Sex:
male/female
Key result
Remarks on result:
no indication of skin sensitisation
Interpretation of results:
GHS criteria not met
Executive summary:

In order to study the prevalence of allergy to onion, skin prick tests were performed. Valdivieso et al., (Bronchial asthma, rhinoconjunctivitis, and contact dermatitis caused by onion; 1994) were able to detect IgE-specific antibodies directed against the onion water extract, with both skin and in vitro tests. None of the four patients experienced a late skin reaction. Furthermore, fresh bulb contains mono and di –saccharides and flavonoids, which are substances not know to be sensitizers.

Endpoint:
skin sensitisation, other
Remarks:
clinical study
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2016
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: data from litterature, no guideline followed. Data used in a weight of evidence strategy.
Qualifier:
no guideline followed
Principles of method if other than guideline:
data from litterature, no guideline followed. Data used in a weight of evidence strategy.
GLP compliance:
not specified
Remarks:
data provided comes from a CIR report which mentions a study, no information on GLP compliance is available.
Type of study:
patch test
Justification for non-LLNA method:
Literature data, used in a weight of evidence approach.
An HRIPT test was performed on 102 volunteers with skin cleansing product containing 1% of Citrus limon (lemon) fruit water.
Species:
other: human
Strain:
not specified
Sex:
male/female
Key result
Remarks on result:
no indication of skin sensitisation
Interpretation of results:
GHS criteria not met
Executive summary:

An HRIPT test was performed on 102 volunteers with skin cleansing product containing 1% of Citrus limon (lemon) fruit water. Test material did not induce sensitization (Cosmetic Ingredient Review, Safety Assessment of Citrus Fruit-Derived Ingredients as Used in Cosmetics, 2016).

Fresh pulp of Citrus limon brings citric acid, also not know to be allergenic.

Moreover, it is well known that the lemon sensitizer substances are present in the peel. None of those were found in pulp (Compendium of botanicals reported to contain naturally occuring substances of possible concern for human health when used in food and food supplements, 2012).

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

Justification for classification or non-classification