Octanoyl Hydroxamic Acid: A Promising Preservative Synergist in Cosmetics – Applications, Safety, and Regulatory Considerations

Application status of octanoyl hydroxamic acid in cosmetics

Cosmetics are rich in nutrients, such as water, various types of oils and fats, and various functional additives, which can provide rich carbon and nitrogen sources for microorganisms, and thus easily lead to microbial contamination, affecting product quality and even consumer safety and health. In order to prevent cosmetics from primary or secondary pollution, cosmetics need to add preservatives to inhibit the growth of microorganisms within the product, reproduction, and extend the shelf life of the product. According to the U.S. FDA and CTFA, there are more than 100 kinds of preservatives allowed to be used in cosmetics. China’s 2015 edition of the Technical Code for Cosmetic Safety includes 51 permitted preservatives and restricts the maximum use amount, conditions of use and types of cosmetics. As cosmetic regulators in various countries pay increasing attention to the issue of cosmetic preservatives and continuously revise relevant regulations, and as consumers’ awareness of product safety increases and their demand for product safety becomes higher and higher, cosmetic manufacturers also put forward higher requirements for preservatives.

Traditional preservatives can meet the product requirements for bacteriostatic properties, but most of the traditional preservatives have certain safety risks, such as methylisothiazolinone has been repeatedly reported to cause consumers to suffer from skin contact dermatitis, the European Union Scientific Committee on Consumer Safety (SCCS) carried out many safety risk assessment, on July 6, 2017, the European Union issued a regulation (EU) 2017/1224 will be the maximum concentration of methylisothiazolinone. thiazolinone’s maximum use concentration from the original 0.01% down to 0.0015%, and banned for use in resident cosmetics; formaldehyde is an extremely effective preservative, but it has a high risk of carcinogenicity and a very low safety, and formaldehyde retardant class preservatives achieve the effect of bacterial inhibition through the release of formaldehyde, there is a potential for sensitization; Brobol is decomposition sterilization, easy to form carcinogenic nitrosamines; halogenated classes of bacteriostatic agents Strong irritation and high sensitization rate. Therefore, safe and efficient preservatives or raw materials with antiseptic effects are becoming more and more popular among manufacturers, such as p-hydroxybenzene derivatives, diols, amphiphilic molecules with medium carbon chains, organic acids, antimicrobial peptides and so on.

Octanoyl hydroxamic acid, also known as octanoyloxamic acid, is a kind of organic acid with strong chelating ability for metal ions, so it is often used as a trapping agent in the field of mineral flotation, and it is also found to be added to animal feed as a growth promoter. In recent years, it has been more and more widely used in cosmetics. In addition to being used as a chelating agent in cosmetics, it has also been used as a tyrosinase inhibitor in whitening products, and even as a preservative synergist in a wide range of cosmetic applications.

Caprylhydroxamic acid INCI name: Caprylhydroxamic Acid; white or off-white crystals, soluble in propylene glycol, glycerol, surfactants, solubility in water 1.55 g/L (23 ℃); melting point / freezing point 79.0 ℃ -81 ℃; partition coefficient (log Kow, 25 ℃): 1.66.

The antibacterial property of octanoyl hydroxamic acid can be traced back to the 2012 invention patent CN 102920612A by Xu Jinrong et al. The patent discloses a broad-spectrum antibacterial cosmetic preservative, in which the content of octanoyl hydroxamic acid is 8-12%, which can effectively inhibit Gram-negative and positive bacteria, molds, and yeasts, and the antibacterial property is not affected by the surfactants, proteins, and herbal additives in cosmetics It can effectively inhibit Gram-negative, positive bacteria, molds and yeasts. In recent years, it has been widely used in cosmetics for its antibacterial properties.

Use of octanoyl hydroxamic acid in cosmetics

In 2019, the U.S. Food and Drug Administration VCRP data statistics show that there are currently 227 formulations containing octanoyl hydroxamic acid, which are used in eye products, lip products, baby products, laundry products, and products that come into contact with mucous membranes. There are many cases in the open literature where octanohydroxamic acid has been used in combination with other preservatives, and the combined preservative systems have been used in a variety of formulations. Studies have shown that octanoyl hydroxamic acid can be used in small amounts to synergize with other preservatives. Li Xinhang et al. preferred 0.056 % octanoyl hydroxamic acid with ethylhexylglycerol and glyceryl caprylate, and conducted a comprehensive evaluation of the compounded preservative system through the preservative challenge experiment and the allergic patch experiment, and the results showed that the preservative system was used in lotions, O/W lotions, O/W creams, W/O cream formulations, and W/O cream formulations. cream, W/O cream formulations with better antimicrobial performance and mild and non-irritating. Zhang Han et al. studied the microbial challenge test of octanoyl hydroxamic acid and glyceryl caprylate composite antiseptic in five cosmetic dosage forms such as aqueous, cream, gel, shampoo, and conditioner, and found that the composite antiseptic system had good antiseptic effect. Through the chicken embryo chorionic villous allantoic membrane vascular test on the mask serum containing this antiseptic system, the results showed no damaging stimulation, at this time the capillary did not have hemorrhagic damage; and the results of the mask serum containing 0.1% MIT showed more serious damaging stimulation, at this time the capillary appeared to be more serious hemorrhagic damage. In another literature report, by exploring the antibacterial effect of a novel compound moisturizing preservative composed of ethylhexylglycerol, glyceryl caprylate, 1,2-hexanediol, caprylohydroxamic acid and 1,3-propanediol in aqueous, emulsions, face masks, creams and other skincare products, the results showed that the compounded antiseptic system in different dosage forms of cosmetic products can show a good effect of antibacterial inhibition. In particular, octanoyl hydroxamic acid can be added to cosmetics at an amount of 0.045 % to 0.063 % to achieve synergistic effects with other preservatives. U.S. Patent Nos. 110,351,523 and 10,407,528 also refer to the use of octanohydroxamic acid or a mixture of octanohydroxamic acid and glyceryl caprylate as a preservative when added to sunscreen formulations.

Determination of octanoyl hydroxamic acid content in cosmetics

Although octanohydroxamic acid is not included in the list of preservatives in the Technical Code for the Safety of Cosmetics (2015 edition), due to its good synergistic preservative properties, some cosmetic manufacturers add it to cosmetics to function as a preservative, and at the same time, claim that their products do not contain preservatives in order to publicize the “no-additive” effect. Therefore, the determination of octanohydroxamic acid in cosmetics can provide technical support for the quality control of regulatory authorities and cosmetic enterprises, and protect the safety and interests of consumers. Li Fajin et al. established a high performance liquid chromatographic (HPLC) method for the determination of octanohydroxamic acid in cosmetics, and investigated the effects of mobile phase, detection wavelength, sample extraction solvent and ultrasonic extraction time on the results. The method is characterized by high recoveries and good reproducibility for different cosmetic dosage forms, such as liquid, cream and gel, etc. In addition, phenoxyethanol, methyl p-hydroxybenzoate and propyl p-hydroxybenzoate, which are often used in combination with octanohydroxamic acid, do not interfere with each other, and do not affect the determination of the target substances. Mo Tingyuan et al. used methanol as the extraction solvent and ultrasound as the extraction method to determine the content of octanohydroxamic acid in 20 batches of cosmetic samples of different dosage forms by high performance liquid chromatography, and the results showed that octanohydroxamic acid was detected in moisturizing creams, essence milks, and softening lotions, with the percentages of 0.018 %, 0.037 %, and 0.019 %, respectively.

Cosmetic safety of octanoyl hydroxamic acid

The safety of octanoyl hydroxamic acid, whether used as a chelating agent or preservative in cosmetics, is also of great concern. As early as 2012, the National Industrial Chemical Notification and Assessment Service (NICNAS) of Australia assessed the human health risk of octanoyl hydroxamic acid. A 20 % solution of octanohydroxamic acid was tested using the Bovine Corneal Opacity and Permeability (BCOP) test and under the test conditions octanohydroxamic acid was not considered to be a corrosive or severe irritant. 100 % octanohydroxamic acid was also demonstrated to be a non-irritant or minimally irritant by the EpiOcular™ corneal model. Octanohydroxamic acid is non-eye irritant as demonstrated by two in vitro eye irritation tests. The Chinese patent CN 102920612 A proposes a compound preservative containing 8-12 % octanoyl hydroxamic acid, which was shown to be minimally irritating to acute eye irritation in rabbits at a use level of 1.2 % by a Draize test, but this could not be determined whether it was brought about by octanoyl hydroxamic acid in the preservative or by phenylethanol. For this product, Xu Jinrong et al. also did an acute skin irritation test, which showed that the subject sample did not cause skin irritation in a single contact with rabbits.In June 2019, the U.S. Cosmetic Ingredient Evaluation (CIR) also released a draft of the Safety of Octanoyl Hydroxamic Acid for Cosmetic Use, and although no final conclusions have been reached yet, a lot of experimental data is worth paying attention to. Applied to an EpiDerm™ skin model reconstructed with keratin-forming cells and tested according to the standard OECD TG 439, octanoyl hydroxamic acid was classified as a non-irritant.

There are no national or international reports of adverse reactions such as contact dermatitis due to octanohydroxamic acid, except for a Finnish Apobase containing octanohydroxamic acid which has been shown to cause contact dermatitis.CIR has collected reports and results of human repetitive injury patch tests (HRIPT) using octanohydroxamic acid in a wide range of concentrations, from a minimum of 0.105 % to a maximum of 100 % undiluted octanohydroxamic acid. 100 % undiluted octanohydroxamic acid powder, and from 52 to 109 volunteers, during which scattered, transient, barely observable mild erythema and occasional edema were noted on the skin of some of the volunteers; the researchers indicated that the results of the test performed in the same manner were not proportional to the dilution concentration, either in terms of the number of positive reactions or the degree of reaction. The results of the HRIPT test showed that octanohydroxamic acid is not an irritant or sensitizer.

NICNAS calculated the MOE (margin of exposure) by assuming that a 60-kg female is exposed daily to a concentration of octanohydroxamic acid and NOAEL in 15 cosmetic products, both leave-on and leave-off, and concluded that the use of octanohydroxamic acid in cosmetic products up to a maximum concentration of 0.3 % is not considered to be a safety concern.

With the gradual improvement of people’s requirements for cosmetics, safety and low irritation have become the basic elements of cosmetics, and substances with high irritation, high risk, and low safety will be slowly replaced and eliminated. Octanohydroxamic acid is not listed in the preservatives list or other banned or restricted list in China or abroad, so it is subject to certain limitations when listed as a preservative in the domestic cosmetic filing, and there are fewer data reports on its safety in China. And the study shows that octanoyl hydroxamic acid has no eye irritation, no skin irritation, no potential sensitization, although it is difficult to achieve good bacterial inhibition when used alone, but with the same natural source of low irritant substances ethylhexylglycerol, glyceryl caprylate used in conjunction with the growth of microorganisms can be effectively inhibited; and with the use of traditional preservatives compounded to effectively reduce the dosage of conventional preservatives, so as to reduce the overall irritation and It can effectively solve the problem of cosmetic safety, and has a wide range of application prospects in cosmetics.