Application of the threshold of toxicological concern approach for the safety evaluation of calendula flower (Calendula officinalis) petals and extracts used in cosmetic and personal care products

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Abstract

Calendula flower (Calendula officinalis) (CF) has been used in herbal medicine because of its anti-inflammatory activity. CF and C. officinalis extracts (CFE) are used as skin conditioning agents in cosmetics. Although data on dermal irritation and sensitization of CF and CFE’s are available, the risk of subchronic systemic toxicity following dermal application has not been evaluated. The threshold of toxicological concern (TTC) is a pragmatic, risk assessment based approach that has gained regulatory acceptance for food and has been recently adapted to address cosmetic ingredient safety. The purpose of this paper is to determine if the safe use of CF and CFE can be established based upon the TTC class for each of its known constituents. For each constituent, the concentration in the plant, the molecular weight, and the estimated skin penetration potential were used to calculate a maximal daily systemic exposure which was then compared to its corresponding TTC class value. Since the composition of plant extracts are variable, back calculation was used to determine the maximum acceptable concentration of a given constituent in an extract of CF. This paper demonstrates the utility and practical application of the TTC concept when used as a tool in the safety evaluation of botanical extracts.

Introduction

Calendula officinalis (CF) also known as Garden Marigold, God-Bloom, Holligold, Marigold, Marybud, and Pot Marigold, is part of the botanical family of Asteraceae/Compositae (Jellin et al., 2003). The dried flower is used as a spice and is considered to be generally recognized to be safe (GRAS) by the food and drug administration (FDA) (Food and Drug Administration, 2007) and the Flavors and Extracts Manufacturers Association (FEMA) (FEMA number 2658) (Hall and Oser, 1965). It is used topically as a natural anti-inflammatory medicine and for poorly healing wounds and leg ulcers. The dosages cited are 2–4 mL of tincture diluted to 250–500 mL with water or 2–5 g of herb in 100 g of ointment (Jellin et al., 2003). Other topical uses include treatment for 1st degree burns and scalds, bruises, boils, and rashes (Lueng and Foster, 1996, Blumenthal et al., 2000). A tea made from 1 to 2 g of the flower in 150 mL of boiling water has also been used up to three times a day as an antispasmodic (Jellin et al., 2003). Other oral uses include alleviation of the discomfort associated with stomach ulcers and inflammation of the oral and pharyngeal mucosa (Lueng and Foster, 1996, Blumenthal et al., 2000). Calendula preparations are therefore regarded as traditionally used medicines by the European Medicines Agency (EMEA) (EMEA, 2008a, EMEA, 2008b). In cosmetic or personal care preparations calendula extracts are used as skin conditioning agents at concentrations ranging up to 1% but are generally below 0.1% (Anonymous, 2008). All together, these data allow one to conclude that calendula extracts should be considered as having a long history of safe use as defined by Constable et al. (2007).

UNITIS, the European Organization of Cosmetic Ingredients Industries and Services, has provided the cosmetic ingredient review (CIR) (report available through the Cosmetic Ingredient Review, Washington, DC) with an extensive list of chemicals that comprise the calendula plant along with concentration ranges (UNITIS, 2006). Table 1 presents a summary of this list of chemical constituents that was derived through literature search. The concentrations cited were found in relevant papers and do not represent analytical work done by UNITIS. To supplement the UNITIS report additional sources were used (Duke, 1996, Kishimoto et al., 2005, Alonso, 2004, Valdes and Garcia, 1999, Korakhashvili et al., 2007, Blumenthal et al., 2000, EMEA, 2008a, EMEA, 2008b). These documents serve as the basis for the safety assessment of cosmetic uses of CF presented in this paper. Calendula flower extract (CFE) is not a single entity but rather a number of materials that differ by extraction method (organic solvent, CO2, etc.) and possibly plant part resulting in differing chemical compositions. In addition, extracts can be further manipulated to increase the yield of specific materials. This presents a challenge for the safety evaluation of CFE in that concentrations of various components may differ from those found in CF.

The threshold of toxicological concern (TTC) is a concept that has evolved for the evaluation of food chemicals and flavoring materials. TTC is a concept that is based on the assumption that for all chemicals there is a level of exposure below which there is no appreciable risk to human health. The TTC concept as presented in this paper refers only to systemic toxicity. This concept has been reviewed in a concise manner by Renwick, 2004, Kroes et al., 2005. In the TTC process a decision tree approach is used to place chemicals into three classes with the following thresholds for toxicity (Cramer classes) (Cramer et al., 1978):

  • Class I – 1800 μg per person/day.

  • Class II – 540 μg per person/day.

  • Class III – 90 μg per person/day.

It should be noted that Munro has recently recommended that Class III be changed to 180 μg/day (Munro et al., 2008).

Kroes et al. (2007) extended the TTC concept to the safety evaluation of cosmetic ingredients. This publication also describes in detail a method to determine default values for percutaneous absorption of chemicals on the basis of their molecular weight and log P values (Kroes et al., 2007). Justification for using these default values and their conservative nature is also outlined in this publication. The Kroes et al. (2007) paper also presents the justification for using the absorption factors in calculating a systemic equivalent dose in comparison to the oral TTC approach. The use of TTC for dermal application of chemicals and of specifically for cosmetics is further supported by Munro et al. (2008). Approaches which refer to the TTC concept have also been used to evaluate the safety of complex natural flavors and essential oils used as flavorings in foods (Smith et al., 2004, Smith et al., 2005).

This paper evaluates the use of the TTC concept to evaluate the safety in use of CF and CFEs as cosmetic ingredients and suggests that this concept can be used for other well defined plant extracts.

Section snippets

Methods

From the various reports used the fractions, sub-fractions, and compounds found in CF flowers were identified. These components comprise approximately 43–72% of the dried flowers, also referred to as petals. The remainder of the material in the petals is comprised of inert plant material and residual moisture. A ChemID (US National Library of Medicine, 2008) search was done for each of the chemicals in the calendula flower. For those materials that were identified In ChemID, the SMILES notation

Results

The following classes of materials were not considered relevant to the safety evaluation of calendula extracts:

  • Mineral matter (∼9%).

  • High molecular weight carbohydrates (e.g. mucilage) (12–25%).

  • Fatty acid esters (reviewed by CIR, food additives, etc.) (5%).

  • Amino acids (4.5%).

  • Resins (3.4%).

  • Components with MW > 1000 (skin penetration is negligible).

  • Inert plant material such as cellulose.

  • Components present at <0.5%.

Table 2 presents the results of the TTC analysis based upon the maximal concentration

Discussion and conclusion

Historically, the TTC concept has been used extensively in the food industry to establish the safety of materials used as indirect food additives. The flavor industries (Smith et al., 2004, Smith et al., 2005), the WHO (JECFA, 1974, Renwick, 2004) and EFSA have adapted this procedure for the safety evaluation of food flavoring substances. More recently, the TTC concept has been adapted for the evaluation of topically applied cosmetic ingredients (Kroes et al., 2007) and for the safety

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgements

The authors would like to thank Dr. Stephanie Ringeissen, Life Sciences Research, L’Oreal for her assistance with the preparation of this paper.

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