Kojic acid is also called aspergillic acid with its chemical name of 5-hydroxy-2-hydroxymethyl-4H-pyran-4-one, and its chemical structural formula is as follows. Kojic acid is a colorless prismatic crystal, which is easily soluble in water, alcohol and acetone, slightly soluble in ether, ethyl acetate, chloroform and pyridine, but hardly soluble in most other solvents. Kojic acid is unstable and sensitive to light and heat. It is easy to be oxidized in air, and can also form chelate compound with metal ions. Kojic acid can inhibit tyrosinase activity during the formation of melanin, and has obvious whitening effect without inhibiting other enzymes. Now it has been widely used in daily chemical industries such as skin whitening and sun care cosmetics, solvents and toothpastes.

1. Preparation for the fermentation of kojic acid

Kojic acid is a secondary metabolite derived from microorganisms, which has no physiological toxicity and simple structure. Due to the instability of its enol structure, however, it is often modified and derived as a skeleton, such as synthesizing kojic acid dipalmitate and kojic acid ester. These derivatives not only improve the solubility and stability of kojic acid in oily cosmetics, but also greatly improve its biological activity.

After kojic acid was first found in soy sauce brewed by aspergillus oryzae, many researchers started to isolate kojic acid from fermentation products of some strains of aspergillus flavus, and its yield was higher than that of aspergillus oryzae. However, while the fermentation of aspergillus flavus produces kojic acid, it also produces aflatoxin, a strong carcinogen. While conducting studies on 149 strains of aspergillus oryzae and 46 strains of aspergillus flavus, the researchers found that all aspergillus flavus produced kojic acid and 34 strains produced aflatoxin at the same time. However, only 105 strains of aspergillus oryzae produced kojic acid and none of them produced aflatoxin. Therefore, when choosing aspergillus flavus as strains to produce kojic acid, great importance should be attached to its security.

In order to improve the yield of kojic acid, scholars at home and abroad have done a lot of research, mainly including strain breeding and the optimization of fermentation method. Aspergillus strains, as kojic acid producing strains, were mutagenized by different physical and chemical methods, and the kojic acid yield was improved in different degrees. However, with further studies on mutagenesis, the effect of increasing yield by mutagenesis has obviously decreased. In the process of strain breeding, there are some limitations, such as random mutagenesis methods, difficulty in mastering the direction and difficulty in screening ideal individuals. In addition, the sensitivity of strains has been decreased and its tolerance has been improved through multiple rounds of screening. Therefore, it is necessary to find new approach to increase the yield of kojic acid.

2. Safety of kojic acid

In the early 1990s, Japan firstly added kojic acid to cosmetics as a skin whitening ingredient. It was used to whiten skin and remove color spots because it can inhibit tyrosinase and block the intermediate production produced by melanin. Subsequently, it was found that kojic acid may cause cancer. In 2003, the Japanese government banned the import and production of cosmetics containing kojic acid. However, due to insufficient evidence, the regulations on adding kojic acid to cosmetics were reopened in 2005. Although there was no clear restriction standard of kojic acid, its recommended dosage was between 0.1% and 1%. At present, kojic acid is listed in the list of three carcinogens published by the International Agency on Cancer Research of the World Health Organization, which has aroused great public concern about the safety of kojic acid. However, there is no management regulation for its use in cosmetics in China's current laws and regulations. There is no doubt that Cosmetics Raw Materials should be safe.

The toxicity kinetics of kojic acid in mice showed that it was rapidly absorbed and distributed to various organs after oral, skin or subcutaneous administration, and the metabolic rate of oral and subcutaneous administration was faster than that of skin exposure. The main metabolites were the combination of sulfuric acid and glucuronic acid, and the contents of kojic acid metabolites were higher in the liver and kidney, which were mainly excreted with urine. In recent years, many foreign scholars have done a lot of research on the genotoxicity, carcinogenicity, embryotoxicity and teratogenicity of kojic acid. The results show that poultries are sensitive to kojic acid, and LD50 of kojic acid taken orally by mice ranges from 1000 to l500mg/kg. With dose of kojic acid orally taken by rats in a range of 300-1000mg/(kg·d), the clinical physiological and biochemical indexes of both male and female rats were normal. No affects was found in autopsy and microscopic observation, and only lymphocytes and leukocytes decreased slightly. The rats were injected with kojic acid at a dose of 300mg/kg every time by intraperitoneal administration. After 14 days, the pathological phenomenon of hepatotoxicity was found in rats. However, the research results of kojic acid on the fertility and embryo of rats are uncertain.

It is undisputable that kojic acid can induce gene mutation of some strains of salmonella and bacillus subtilis. But researchers are still debating on whether kojic acid has the mutagenic effect on biological genetic material. Many studies have shown that thyroid hyperplasia caused by kojic acid has nothing to do with genotoxic pathway. A sustained high dose of kojic acid can inhibit the absorption of iodine in rats and rats, and induce thyroid hyperplasia and adenoma. Adding kojic acid to food may cause thyroid tumor. However, at present, the experiment is limited to rats and rats, and there is no evidence of other animal experiments. However, the concentration of kojic acid in food is extremely low, so it should be safe to use it under normal circumstances.

3. Current situation of kojic acid management in international cosmetics regulations

There is no provision on kojic acid in EU Cosmetics Regulation (EC) No.1223/2009. For the safety of kojic acid, SCCS pointed out in SCCS/1481/2012 that the kojic acid with the mass fraction of 1.0% is safe in resident cream (not used in a large area) which is often applied to face and hands (kojic acid derivatives are not involved). In 2005, Japan reopened the regulation that kojic acid can be added to cosmetics. Although there is no clear restriction standard of kojic acid, its recommended dosage is between 0.1% and 1%. According to the information provided to FDA by Voluntary Cosmetics Registration Program (VCRP), kojic acid is used in 16 kinds of products such as bath products and skin care products. In the current investigation of the concentration of kojic acid conducted by Personal Care Products Council, it was found that the concentration of kojic acid ranges from 0.1% to 2% by mass fraction, and the maximum concentration is used in face creams, neck creams, lotions and powders. Evaluation conclusion of kojic acid by American Cosmetic Ingredient Review (CIR): Under certain conditions, the maximum permissible concentration of kojic acid (1.0%) is safe.

4. Current situation of cosmetic regulations on kojic acid in China

Kojic acid currently is included in the Catalogue of Already-used Cosmetic (Version 2015), with the serial number of 05453, but there is no management regulation for kojic acid in China's current cosmetics laws and regulations. According to the action mechanism of kojic acid, it can be used as an effective raw material in spot-removing and skin whitening cosmetics. In addition, kojic acid is also used in some non-special cosmetics. Because the concentration of kojic acid exceeds the mass fraction of 1%, side effects such as contact dermatitis can be observed, and the high concentration of kojic acid may have certain cytotoxicity, national regulatory authorities shall pay close attention to the safety assessment and regulations revision of kojic acid in the European Union, Japan, America and other countries and regions, and monitor the risks of cosmetics products containing kojic acid in the market. According to the results of risk monitoring, efforts shall be made to formulate corresponding regulations and set the management limits of kojic acid to better control the risks of using kojic acid and ensure the safety of customers.

Kojic acid has been widely used as a kind of cosmetic raw material, because it can inhibit the tyrosinase activity of melanogenesis enzyme. Besides, it has an obvious skin whitening and spot removing effect and does not inhibit other enzymes. In addition, kojic acid has the properties of bacteriostasis, oxidation resistance, chelation with metal ions, etc. At present, kojic acid and its derivatives have been widely used in foreign countries for antibacterial preservation of food, oxidation resistance and color protection of fruit and vegetables, fresh cut flowers, mushrooms, meat products and aquatic products. Kojic acid is also an intermediate in the production of cephalosporin antibiotics, a raw material for the production of non-toxic and pollution-free pesticides for people and animals, and is used as an iron analysis reagent and a film stain remover.

References:

[1] Shen Minna and Chen Jianhua, Research Progress on Fermentation and Biosynthesis Pathways of Kojic Acid [J]. Chemistry & Bioengineering, 2016, 33 (08): 10-14.

[2] Jiang Liya, and Lan Shile. Research Progress of Kojic Acid Production and Utilization [J]. Journal of Anhui Agricultural Sciences, 2012, 40(21): 11059-11063.

[3] Zeng Zijun, Ruan Haolan, Xiao Shuxiong, Chen Zhanghao, and Fang Jihui. Safety Evaluation of Kojic Acid and Its Current Situation of Cosmetics Regulations [J]. Flavour Fragrance 

About the author:

Xiao Nisha, a food science and technology worker working in a large R&D company of drugs in China, engages in the R&D of nutritious food and functional food.