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Federal Register / Vol. 86, No. 168 / Thursday, September 2, 2021 / Rules and Regulations
B. Toxicological Considerations To establish that butterfly pea flower extract is safe for use as a color additive for the proposed uses, the petitioner used a weight-of-evidence approach based on: 1 Toxicological information about the extracts major coloring component, delphinidin, including a 2013 European Food Safety Authority EFSA review of anthocyanins Ref. 6;
2 a 28-day subacute range finding feeding study in rats; 3 a 90-day feeding study in rats; 4 a bacterial reverse mutation test and an in vitro micronucleous test addressing possible mutagenicity and genotoxicity of butterfly pea flower extract; 5 an in vivo somatic mutation and recombination test conducted on the unprocessed butterfly pea flower parts;
6 in vivo genotoxicity data from published literature on anthothyanins including delphinidin and flavonol components Refs. 7 and 8; 7 clinical human studies of anthocyanins including delphinidin and spray-dried butterfly pea flower extract; 8 clinical studies of quercetin and kaempferol, the primary flavonols present; 9 a proteomic assessment of butterfly pea flower extract aimed at establishing that cyclotides found in the tissues of Clitoria ternatea are not present in the butterfly pea flower extract; and 10 an allergenicity assessment of butterfly pea flower extract.
We reviewed the oral toxicity studies and agree with the petitioners conclusions that the no observed adverse effect level in the 90-day study is the highest dose tested 3,500 mg/kg/
d of butterfly pea flower extract, which is nearly 500-fold of the 90th percentile daily exposure for U.S. population 2
years and older Ref. 9. While chronic studies were not provided by the petitioner nor available from the published literature, we believe that chronic toxicity from the intended use of butterfly pea flower extract is unlikely because: 1 We did not identify any potential toxicity effects associated with the use of either butterfly pea flower extract or its anthocyanins and flavonol components from literature that warrant further chronic toxicity studies Refs. 9 and 10;
2 the systemic oral absorption of anthocyanins and flavonols is generally low Ref. 9; 3 there are available human clinical studies indicating that the main anthocyanins and flavonol components of butterfly pea flower extract are well tolerated in humans Ref. 9; and 4 anthocyanins and flavonols are naturally present and widely distributed in many plants used as food, and the exposures to
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anthocyanins and flavonols from the use of butterfly pea flower extract were estimated to be comparable or lower than the exposure from a typical diet Ref. 11.
We also did not find any scientific data suggesting reproductive or developmental toxicity; moreover, the genotoxicity studies demonstrate that butterfly pea flower extract is nonmutagenic and non-genotoxic Ref. 9.
Based on the totality of evidence and a weight of evidence analysis that considered the lack of overall genotoxicity, mode of action, and the level of exposure, we conclude that butterfly pea flower extract is not likely to pose a carcinogenic risk to humans at its intended use levels Refs. 9 and 10.
Among the available relevant clinical studies, one study of butterfly pea flower extract indicated no acute adverse effect at doses up to 2 grams per person. Other clinical studies, using either anthocyanins or flavonols, suggested tolerance at doses much higher than the exposure level from the consumption of butterfly pea flower extract under the intended condition of use Ref. 9.
The petitioner provided analytical evidence demonstrating that the cyclotides identified in butterfly pea flower petals were not detected in the butterfly pea flower extract. Therefore, there is no toxicity concern for cyclotides from the consumption of the extract Ref. 9.
Although there is no evidence in the scientific literature specifically suggesting that either Clitoria ternatea flowers or the coloring component delphinidin is associated with allergic or hypersensitive reactions, we note that butterfly pea flower extract contains 8 to 12 percent protein by weight. To address the allergenicity potential of butterfly pea flower extract, the petitioner provided bioinformatic analyses of the 193 protein sequences of Clitoria ternatea identified in the National Center for Biotechnology Information protein database. These protein sequences were compared for similarity with the known allergenic protein sequences collected in the AllergenOnline database Ref. 12. The analysis revealed five protein sequence matches defined as 35 percent or higher identity over an 80-amino-acid sliding window; however, these proteins are expected to be over 5,000 Da and not likely to pass through the 2,500 Da ultrafiltration system used in the manufacturing process. To mitigate the possible risk that allergenic proteins and other large peptides might pose, our regulation at 21 CFR 73.69a1 requires that the aqueous extract used to produce
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the color additive undergo ultrafiltration. We agree with the petitioner that the totality of the evidence supports the conclusion that it is extremely unlikely that the proteins in butterfly pea flower extract could act as allergens Ref. 9.
V. Conclusion Based on the data and information in the petition and other available relevant information, we conclude that the petitioned use of butterfly pea flower extract as a color additive in: Alcoholic beverages, sport and energy drinks, flavored or carbonated water, fruit drinks including smoothies and grain drinks, carbonated soft drinks fruitflavored or juice, ginger ale, and root beer, fruit and vegetable juice, nutritional beverages, chewing gum, teas, coated nuts, liquid coffee creamers dairy and non-dairy, ice cream and frozen dairy desserts, hard candy, dairy and non-dairy drinks, fruit preparations in yogurts, and soft candy is safe, provided the amount of butterfly pea flower extract does not exceed levels consistent with good manufacturing practice.
We further conclude that this color additive will achieve its intended technical effect and is suitable for the petitioned use. Therefore, we are amending the color additive regulations in part 73 to provide for the safe use of this color additive as set forth in this document. In addition, based on the factors in 21 CFR 71.20b, we conclude that batch certification of butterfly pea flower extract is not necessary to protect the public health.
VI. Public Disclosure In accordance with 71.15 21 CFR
71.15, the petition and the documents that we considered and relied upon in reaching our decision to approve the petition will be made available for public disclosure see FOR FURTHER
INFORMATION CONTACT. As provided in 71.15, we will delete from the documents any materials that are not available for public disclosure.
VII. Analysis of Environmental Impact As stated in the November 13, 2018, Federal Register notification of filing, the petitioner claimed that this action is categorically excluded under 25.32k 21 CFR 25.32k because butterfly pea flower extract would be added directly to food and is intended to remain in the food through ingestion by consumers and is not intended to replace macronutrients in food. We further stated that if FDA determines a categorical exclusion applies, neither an environmental assessment nor an
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