Registration Dossier

Administrative data

Endpoint:
skin sensitisation: in vitro
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
Yucca schidigera Ortgies is a herbaceous plant from the family Asparagaceae, native to the deserts of the south-western United States and northern Mexico. Due to the antiprotozoal and antifungal properties and hormone-stimulating effects it has been used safely to enhance performance as feed material for livestock as well as food material for humans (I. Kucukkurt et al. / Revista Brasileira de Farmacognosia 26 (2016) 246–250). Yucca schidigera (Agavaceae) is one of the major commercial source of steroidal saponins. Two products of yucca are available on the market. These include dried and finely powdered logs (yucca powder) or mechanically pressed and thermally condensed juice (yucca extract). These products possess the GRAS label (Generally Recognized As Safe) given by US FDA which allows their use as foaming agent in soft drink (root beer), pharmaceutical, cosmetic, food, and feeding-stuffs industries. (Piacente S et al., Phytochemistry Reviews (2005) 4: 177–190).
As to the application of saponins to foods and cosmetics, it is indispensable that a plant must have a long history of human use as foodstuffs or ingredients of cosmetics, and their safety should be officially guaranteed. Yucca species (Agavaceae), grows widely in North and Central America. Mohave yucca, Y. schidigera, has been used as a foodstuff and folk medicine by Native Americans as well as early California settlers to treat a variety of ailments including arthritis and inflammation, and is approved for use in food and beverages by the U.S. Food and Drug Administration (FDA) under Title 21 CFR 172.510, FEMA number 3121. (Tamura Y et al., Chapter 5, Application of Saponin-Containing Plants in Foods and Cosmetics, in: Alternative Medicine, http://dx.doi.org/10.5772/53333)
According to 21CFR ,Sec. 172.510 Natural flavoring substances and natural substances used in conjunction with flavors. (https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=172.510), natural flavoring substances and natural adjuvants may be safely used in food in accordance with i.a. the following conditions.
In the appropriate forms (plant parts, fluid and solid extracts, concentrates, absolutes, oils, gums, balsams, resins, oleoresins, waxes, and distillates) they consist of one or more of the following, used alone or in combination with flavoring substances and adjuvants generally recognized as safe in food, previously sanctioned for such use, or regulated in any section of this part. This list includes i.a. Yucca brevifolia Engelm and Yucca schidigera Roezl ex Ortgies (Y. mohavensis Sarg.). These substances are not allowed to endanger human health, so there has been no indication that the substance could be potentially skin sensitizing. Further, with regard to the use as traditional medicinal plant, there were no incidences of human contact dermatitis or any other indication of a skin sensitization potential reported.
According to the CosIng Database (European Commission database for information on cosmetic substances and ingredients), Yucca Schidigera Root Extract is used for Skin conditioning, Yucca Schidigera Extract for cleansing, masking, skin protection and as surfactant. According to Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on cosmetic products, the cosmetic product safety report shall i.a. contain the toxicological profile of substance contained in the cosmetic product for all relevant toxicological endpoints. A particular focus on local toxicity evaluation (skin and eye irritation), skin sensitisation, and in the case of UV absorption photo-induced toxicity shall be made. The cosmetic product shall be safe and be used without any harm to the consumer. Hence, as a cosmetic ingredient, Yucca extract must not be sensitizing to human skin and so be harmful to consumers. Indeed, also here there could no indication be found that Yucca extract is potentially sensitizing.
In summary, it can be concluded that Yucca extract would not be sensitizing to human skin, and testing can be waived according to REACH Annex XI 1.1 use of existing data.


In addition to the rationale outlined above, the waiving criteria according to Annex VII may apply, in combination with the fact that skin sensitization testing via a defined approach is not feasible (use of existing data). According to REACH Annex VII column 1, the following tests are required: (a) molecular interaction with skin proteins; (b) inflammatory response in keratinocytes; and (c) activation of dendritic cells. According to column 2, the(se) test(s) do not need to be conducted if:
— an in vivo study according to point 8.3.2 is available, or
— the available in vitro/in chemico test methods are not applicable for the substance or are not adequate for classification and risk assessment according to point 8.3.
If information from test method(s) addressing one or two of the key events in column 1 already allows classification and risk assessment according to point 8.3, studies addressing the other key event(s) need not be conducted.

The substance is an UVCB (substances of unknown or variable composition, complex reaction products or biological materials).According to OECD Test guideline 442C, the prediction model cannot be used for complex mixtures of unknown composition or for substances of unknown or variable composition, complex reaction products or biological materials (i.e. UVCB substances) due to the defined molar ratio of test chemical and peptide. In consequence, a testing according to OECD 442C is not feasible. Similar considerations apply for in silico protein binding estimations.
According to OECD 442D (LuSens), test chemicals that do not act as a sensitiser but are nevertheless chemical stressors may lead to false positive results. The substance is a surfactant and irritating in in vitro tests, so a certain cytotoxicity can reasonably be assumed. Substance with no defined molecular weight may be used, too. Andres E et al. (Toxicology in Vitro 27 (2013) 1220–1225) showed via the KeratinoSens that cytotoxic plant extracts may overestimate the actual sensitizing potential of a sensitizing ingredient, and in general there are limitations to apply in vitro test methods for cytotoxic botanical extracts (Nishijo T, J. Toxicol. Sci., 44 (1), 13-21, 2019). As already indicated above, there are no indications from long-term human exposure that Yucca extract may be skin sensitizing. Only positive results generated with these methods may be used on their own to classify a chemical into UN GHS category 1.
Despite the fact that the logPow should be known for the OECD 442E, it is nevertheless considered that the substance in general is suitable for this test. The logKow should be known because substances with a logPow > 3.5 tend to produce false negative results. The substance is very soluble in water, i.e. 20% in water, so the logPow can reasonably be expected to be way lower than 3.5.
OECD 442E describes three methods. Although the h-CLAT does not explicitly exclude surfactants, the other two, i.e. U-SENS and IL-8 Luc assay, do. So again, the surfactant character and possible cytotoxicity could be an issue.
In summary, in chemico testing is not feasible, and the two remaining in vitro tests may lead to false positive results. So it cannot be proved for sure that the test item is not skin sensitizing as human data indicates.

The OECD draft guideline on defined approaches for skin sensitization outlines 3 approaches:
- The Adverse Outcome Pathway-based "2 out of 3" integrated testing strategy approach to skin sensitization hazard identification based on in chemico (KE 1) and in vitro (KE 2/3) data (BASF) (Bauch et al. 2012; Urbisch et al. 2015). See Part I: Hazard Identification.
This prediction model entails that two concordant results obtained from methods addressing different steps of first three KEs of the AOP determine the final classification. However, in case of two non-concordant results, no final prediction on classification can be made.
- The Sequential testing strategy (STS) for sensitising potency classification based on in chemico (KE 1) and in vitro (KE 3) data (Kao Corporation) (Nukada et al. 2013; Takenouchi et al. 2015). See Part II: Potency Classification.
The test methods used address two key events (KEs) 1 and 3 as defined in OECD Adverse Outcome Pathway (AOP) of skin sensitisation: KE 1 of protein binding is evaluated using the Direct Peptide Reactivity Assay (DPRA; OECD TG 442C); KE 3 of dendritic cell activation is evaluated using the human cell line activation test (h-CLAT; OECD TG442E). As the substance is not suitable for testing for protein binding capacities, this approach cannot be used.
- Integrated testing strategy (ITS) for sensitising potency classification based on in chemico (KE 1), in vitro (KE 3), and in silico (Derek Nexus (ITSv1), OECD Toolbox (ITSv2)) data (Kao Corporation) (Nukada et al. 2013; Takenouchi et al. 2015). See Part II: Potency Classification.
Similarly to the STS, this approach also includes in chemico testing, and cannot be applied. Similarly, due to the lack of an unique chemical structure, in silico modelling is not possible, neither.

So based on the already existing data, in chemico / in silico / in vitro skin sensitization testing cannot be adequately performed to result in clear results, especially not if a negative result is anticipated. So, testing can be waived, as the already available information is sufficient not to classify Yucca schidigera ext. as skin sensitizer.

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion