Formaldehyde-releasing Preservatives Research Articles

Determination of free formaldehyde in cosmetics products through derivatization with 2,4-DNPH using an optimized and validated HPLC-PDA method

AbstractFormaldehyde plays a significant role in the global economy due to its unique chemical properties and widespread use in both the medical field and various industrial sectors. However, formaldehyde (HCHO) is classified as a persistent organic pollutant and is known to be harmful. Exposure to formaldehyde, both direct and prolonged, can cause severe health issues and potentially lead to death. It is recognized as a human carcinogen by numerous organizations and can negatively impact the endocrine system, as well as having mutagenic or teratogenic effects. Formaldehyde has been detected in various matrices at levels exceeding those permitted by international health regulatory bodies. Chromatography, particularly high-performance liquid chromatography (HPLC) coupled with detection methods, is an analytical technique frequently used to determine volatile organic molecules, including formaldehyde. This investigation aimed to develop and validate an assay method to identify and quantify formaldehyde in cosmetic products using HPLC-PDA. The chosen isocratic system consisted of a ZORBAX RX-C8 column (250 mm × 4.6 mm; 5 μm) and a mobile phase mixture of acetonitrile and water in a 55:45 (v/v) ratio, with a flow rate of 1.5 mL min−1. Formaldehyde was detected at 353 nm after derivatization with a 0.1N 2,4-dinitrophenylhydrazine solution, with a retention time of approximately 5.0 min and a total run time of 7.0 min for formaldehyde. The method was validated according to ICH Q2 (R1) guidelines. The validation parameters demonstrated high selectivity, precision (RSD <2%), accuracy (mean recovery of 101.3%), linearity (r > 0.995 in the 1,000–2,400 ppm range), and a limit of quantification (LOQ) of 0.1 ppm. The validated analytical method was applied to 35 cosmetic products. None of these products were labeled as containing formaldehyde, although 6 imported products were labeled as containing formaldehyde-releasing preservatives. The results indicated that 88.6% of the samples tested positive for formaldehyde, with free formaldehyde levels ranging from 20 to 981 ppm. All samples contained formaldehyde levels below the 2000 ppm threshold.

Antimicrobial, Preservative, and Hazard Assessments from Eight Chemical Classes.

Preservatives, such as isothiazolinones and formaldehyde-releasing compounds, provide safety and stability in consumer products by preventing microbial contamination. Yet these ingredients present human and environmental hazards, including allergic contact dermatitis and aquatic toxicity. The development of safer alternatives has been stymied by trade-offs between safety and efficacy. To enable the identification of safer preservatives, substances from eight functional classes were assessed for antimicrobial efficacy and human and environmental hazards. First, 130 substances were evaluated for microbial inhibitory activity against two relevant model microorganisms, Aspergillus brasiliensis (filamentous fungi) and Pseudomonas aeruginosa (Gram-negative bacteria). High-performing compounds within each class were assessed for hazards across a broad suite of human and environmental health end points. Four promising compounds were selected for further testing based on microbial inhibition, hazard profiles, and commercial availability. These ingredients were tested for biocidal activity in model home care formulations using methods adapted from industrial preservative challenge guidelines (USP-51). Two substances were identified, caprylhydroxamic acid and caprylyl glycol, that provided adequate preservation and improved toxicity profiles compared to isothiazolinone and formaldehyde-releasing preservatives. This study highlights trade-offs between antimicrobial activity and hazards across a broad spectrum of chemical classes relevant to safer preservative development.

Quantitative Risk Assessment of Dermal Sensitization Potential Following Use of Shampoo Products Containing the Formaldehyde Releasing Preservative DMDM Hydantoin.

Historically, formaldehyde was used as a preservative in personal care products to extend product shelf-life; however, given its skin sensitization potential it has been phased out of use and replaced with formaldehyde-releasing preservatives, such as Dimethyloldimethyl hydantoin (DMDMH). A relationship has been established between positive patch test results following exposure to DMDMH and previous sensitization to formaldehyde. Upon direct contact with the skin, formaldehyde can react with skin proteins and cause an acute inflammatory reaction, which may progress to skin sensitization following repeated exposure. This quantitative risk assessment (QRA) aimed to assess the risk of skin sensitization induction following use of shampoo products containing the maximum allowable concentrations of DMDMH in formulation (1% w/v), translating to a free formaldehyde concentration of 0.02%. To determine a margin of safety (MOS) for exposure to DMDMH from use of shampoo products, consumer exposure levels (CEL) were estimated based on typical use scenarios and then benchmarked against an acceptable exposure level (AEL). The AEL was derived using a weight of evidence approach where a range of no expected sensitization induction levels (NESILs) was utilized. The MOS values for a shampoo product containing 1% DMDMH (.02% formaldehyde) was above 1 for the typical use scenario indicating a low likelihood of skin sensitization induction among healthy individuals. Thus, it can be concluded that shampoo products containing DMDMH at or below current allowable concentrations are not expected to increase the risk of skin sensitization induction.

Baby wipes and nappy rash - what is the relationship? A review.

Baby wipes are a commonly used cleansing method for infants. A literature review has been performed to assess if using baby wipes is beneficial or harmful compared to water and cloth in terms of nappy rash. This includes a detailed analysis of baby wipe ingredients, as many skin irritants as well as allergens are identified. MedLine, Embase and PubMed were searched and after 420 titles and abstracts were screened, 21 studies remained for inclusion. Baby wipes are deemed as superior to water and cloth in the majority of the literature. However, no definitive conclusion can be drawn as many studies are also industry funded. The most notable allergens identified are fragrances, such as linalool, cocamidopropyl betaine (surfactant), formaldehyde-releasing preservatives and other preservatives, including methylisothiazolinone and methylchloroisothiazolinone. As not all allergens are listed on the label accurately, this can be misleading for the consumer.

Formaldehyde Release From Baby Wipes: Analysis Using the Chromotropic Acid Method

Formaldehyde is a common preservative and strong sensitizer. The aim of the study was to evaluate the release of formaldehyde from baby/toddler wet wipes using the chromotropic acid method (CAM). An online search of best-selling baby wipes was conducted. None declared formaldehyde or formaldehyde-releasing preservatives. Standard CAM procedures were used: a 1 × 1-in square of fresh wipe was placed in a bottle with an open vial of 4 mg/1 mL of chromotropic acid and sulfuric acid solution, sealed, and stored for 48 hours. Formalin and water served as controls. A blinded investigator graded color change (negative, indeterminate, mild, moderate, or strong). For quality control, 20% of all samples as well as all positives were retested. Fifty-one popular and highly reviewed baby and toddler wet wipe products were tested using CAM. Twelve wipes (24%) released formaldehyde (8 mild, 4 moderate/strong). Chromotropic acid method testing of 9 wipes (18%) was indeterminate and 30 (59%) were negative. Almost one quarter of baby/toddler wet wipes released formaldehyde when evaluated with CAM. Patients and clinicians should be aware of this potentially undeclared source of this common allergen.

Determination of free formaldehyde in cosmetics containing formaldehyde-releasing preservatives by reversed-phase dispersive liquid–liquid microextraction and liquid chromatography with post-column derivatization

An analytical method for the determination of traces of formaldehyde in cosmetic products containing formaldehyde-releasing preservatives has been developed. The method is based on reversed-phase dispersive liquid–liquid microextraction (RP-DLLME), that allows the extraction of highly polar compounds, followed by liquid chromatography–ultraviolet/visible (LC–UV/vis) determination with post-column derivatization. The variables involved in the RP-DLLME process were studied to provide the best enrichment factors. Under the selected conditions, a mixture of 500 μL of acetonitrile (disperser solvent) and 50 μL of water (extraction solvent) was rapidly injected into 5 mL of toluene sample solution. The extracts were injected into the LC–UV/vis system using phosphate buffer 6 mmol L−1 at pH 2 as mobile phase. After chromatographic separation, the eluate merged with a flow stream of pentane-2,4-dione in ammonium acetate solution as derivatizing reagent and passed throughout a post-column reactor at 85 °C in order to derivatize formaldehyde into 3,5-diacetyl-1,4-dihydrolutidine, according to Hantzsch reaction, which was finally measured spectrophotometrically at 407 nm. The method was successfully validated showing good linearity, an enrichment factor of 86 ± 2, limits of detection and quantification of 0.7 and 2.3 ng mL−1, respectively, and good repeatability (RSD < 9.2%). Finally, the proposed analytical method was applied to the determination of formaldehyde in different commercial cosmetic samples containing formaldehyde-releasing preservatives, such as bronopol, diazolidinyl urea, imidazolidinyl urea, and DMDM hydantoin, with good relative recovery values (91–113%) thus showing that matrix effects were negligible. The good analytical features of the proposed method besides of its simplicity and affordability, make it useful to carry out the quality control of cosmetic products containing formaldehyde-releasing preservatives.

A proposal to create an extension to the European baseline series.

The current European baseline series consists of 30 allergens, and was last updated in 2015. To use data from the European Surveillance System on Contact Allergies (ESSCA) to propose an extension to the European baseline series in response to changes in environmental exposures. Data from departmental and national extensions to the baseline series, together with some temporary additions from departments contributing to the ESSCA, were collated during 2013-2014. In total, 31689 patients were patch tested in 46 European departments. Many departments and national groups already consider the current European baseline series to be a suboptimal screen, and use their own extensions to it. The haptens tested are heterogeneous, although there are some consistent themes. Potential haptens to include in an extension to the European baseline series comprise sodium metabisulfite, formaldehyde-releasing preservatives, additional markers of fragrance allergy, propolis, Compositae mix, and 2-hydroxyethyl methacrylate. In combination with other published work from the ESSCA, changes to the current European baseline series are proposed for discussion. As well as addition of the allergens listed above, it is suggested that primin and clioquinol should be deleted from the series, owing to reduced environmental exposure.

A dynamic landscape of allergen associations in delayed-type cutaneous hypersensitivity.

Delayed-type hypersensitivity represents a significant clinical and public health challenge. Patients undergoing patch testing may exhibit positive reactions to more than one allergen. It is recognized that reactions to specific pairs of allergens are associated, reflecting a combination of exposure patterns and structural similarity. To explore the influence of time of testing, age, sex and atopy status on allergen pair associations in a series of 45 110 consecutive patients tested over 30 years. Patch test records of all patients undergoing testing with a modified European baseline series between 1985 and 2014 were retrieved from a database at St John's Institute of Dermatology. Reactions were read on days 2 and 4. For each allergen it was recorded whether the allergen was tested and whether the result was positive or negative. This is the largest reported study of patch test allergen pair relationships. Our analysis shows a high degree of variability in allergen pair associations. Rigorous statistical analysis reveals a large number of differences between groups, including a significant increase in the association between formaldehyde and multiple formaldehyde-releasing preservatives over the study period, in addition to pair associations with cobalt and formaldehyde-releasing preservatives. These were present to a significantly greater extent in men than in women. These observations extend our understanding of cutaneous allergy, with implications for both clinical practice and mechanisms of cutaneous hypersensitivity.

Formaldehyde in cosmetics in patch tested dermatitis patients with and without contact allergy to formaldehyde.

Formaldehyde is a well-known contact sensitizer. Formaldehyde releasers are widely used preservatives in cosmetics. To survey the release of formaldehyde in cosmetics brought by patients investigated because of suspected allergic contact dermatitis, to compare it with information given by the manufacturers on the packages, and to investigate whether formaldehyde-allergic patients are potentially exposed to more cosmetics releasing formaldehyde than dermatitis patients without contact allergy to formaldehyde. Cosmetics from 10 formaldehyde-allergic and 30 non-allergic patients (controls) matched for age and sex were investigated with the chromotropic acid spot test, which is a semiquantitative method measuring the release of formaldehyde. Formaldehyde was found in 58 of 245 (23.7%) products. Twenty-six of 126 (20.6%) leave-on products released formaldehyde, and 17 of 26 (65.4%) of these were not declared to contain formaldehyde or formaldehyde releasers. Among the rinse-off products, there were 32 of 119 (26.8%) formaldehyde-releasing products, and nine of 32 (28.0%) of these were not labelled as containing formaldehyde or formaldehyde releasers. Five of 10 formaldehyde-allergic patients brought leave-on products with ≥ 40 ppm formaldehyde, as compared with 4 of 30 in the control group (p = 0.029). Cosmetic products used by formaldehyde-allergic patients that are not declared to contain formaldehyde or formaldehyde-releasing preservatives should be analysed.

North American contact dermatitis group patch test results: 2011-2012.

Patch testing is an important diagnostic tool for assessment of allergic contact dermatitis (ACD). This study documents the North American Contact Dermatitis Group (NACDG) patch-testing results from January 1, 2011, to December 31, 2012. At 12 centers in North America, patients were tested in a standardized manner with a series of 70 allergens. Data were manually verified and entered into a central database. Descriptive frequencies were calculated, and trends analyzed using χ statistics. Four thousand two hundred thirty-eight patients were tested; of these, 2705 patients (63.8%) had at least 1 positive reaction, and 2029 (48.0%) were ultimately determined to have a primary diagnosis of ACD. Four hundred eight patients (9.6%) had occupationally related skin disease. There were 7532 positive allergic reactions. As compared with previous reporting periods (2009-2010 and 2000-2010), positive reaction rates statistically increased for 6 allergens: methylchloroisothiazolinone/methylisothiazolinone (5.0%; risk ratios [RRs]: 2.01 [1.60-2.52], 1.87 [1.61-2.18]), lanolin alcohol (4.6%; RRs 1.83 [1.45-2.30], 2.10 [1.79-2.47]), cinnamic aldehyde (3.9%; 1.69 [1.32-2.15], 1.53 [1.28-1.82]), glutaral (1.5%; 1.67 [1.13-2.48], 1.31 [1.00-1.71]), paraben mix (1.4%; 1.77 [1.16-2.69], 1.44 [1.09-1.92]), and fragrance mix I (12.1%; RRs 1.42 [1.25-1.61], 1.24 [1.14-1.36]). Compared with the previous decade, positivity rates for all formaldehyde-releasing preservatives significantly decreased (formaldehyde 6.6%; RR, 0.82 [0.73, 0.93]; quaternium-15 6.4% RR 0.75 [0.66, 0.85]; diazolidinyl urea 2.1%; RR, 0.67 [0.54, 0.84]; imidazolidinyl urea 1.6%, 0.60 [0.47, 0.77]; bronopol 1.6%; RR, 0.60 [0.46, 0.77]; DMDM hydantoin 1.6%; RR, 0.59 [0.54, 0.84]). Approximately a quarter of patients had at least 1 relevant allergic reaction to a non-NACDG allergen. In addition, approximately one-fourth to one-third of reactions detected by NACDG allergens would have been hypothetically missed by T.R.U.E. TEST (SmartPractice Denmark, Hillerød, Denmark). These data document the beginning of the epidemic of sensitivity to methylisothiazolinones in North America, which has been well documented in Europe. Patch testing with allergens beyond a standard screening tray is necessary for complete evaluation of occupational and nonoccupational ACD.

화장품 중 포름알데히드 함유량 조사

포름알데히드는 그 자체가 보존제로 또는 다른 보존제로부터 유리된 형태로 화장품에 일반적으로 존재한다. 포름알데히드는 낮은 농도로도 민감한 피부 반응을 일으킬 수 있으므로 화장품에서 그 사용을 규제하고 있다. 본 연구에서는 팩 및 마스크와 같은 화장품 114 품목을 시중에서 구입하여 포름알데히드의 함량을 분석하였다. 검사 품목의 36%에서 <TEX>$0.3{\sim}9.7{\mu}g/mL$</TEX> (ppm) 수준의 포름알데히드가 검출되었다. 포름알데히드 유리 보존제를 함유한다고 표시되어 있는 12개 제품의 포름알데히드 함량을 조사하였다. Imidazolidinyl urea를 사용한 화장품 10품목과 1,3-Dimethylol-5,5-dimethylhydantoin (DMDM hyantoin)을 사용한 화장품 2품목에서 평균 <TEX>$1.7{\mu}g/mL$</TEX> (ppm)의 포름알데히드가 검출되었다. 식품의약품안전청 고시 최대 허용 포름알데히드 농도 0.2 % (2,000 ppm)을 고려할 때, 이번 조사에서 분석한 화장품에서는 비교적 낮은 수준의 포름알데히드 함량을 보였다. Formaldehyde is commonly present in cosmetic products as an ingredient intended to preserve cosmetic raw materials or as a liberated product from other formaldehyde-releasing preservatives. Since even low level of formaldehyde can elicit a dermatological reactions in sensitized individuals, there has been a tendency to restrict and regulate the use of formaldehyde in cosmetic products. In this study, we determined formaldehyde content in 114 commercial cosmetic products such as packs and masks. Formaldehyde was detected at the level ranging from 0.3 to <TEX>$9.7{\mu}g/mL$</TEX> (ppm) in 36 % of the tested cosmetic products. We investigated formaldehyde content of twelve products specifying to contain formaldehyde-releasing preservatives on their labels. In eleven of ten imidazolidinyl urea-containing and two 1,3-Dimethylol-5,5-dimethylhydantoin (DMDM hyantoin)-containing products, average of <TEX>$1.7{\mu}g/mL$</TEX> (ppm) formaldehyde level was detected. The formaldehyde levels detected in our tested products are low when compared with the maximum authorised concentration 0.2 % (2000 ppm) of formaldehyde in cosmetics according to the Korean Food and Drug Administration notice.

Physician-Patient Agreement in the Assessment of Allergen Relevance

The efficacy of patch testing may be enhanced by data allowing the physician to estimate the likelihood that results of a patch-test reading are relevant to a patient's dermatitis. The goal of this study was to compare the rates of agreement between the physician's assessment of relevance at the time of final reading and the patients' report 3 months to 3 years later in regard to whether avoidance of an allergen was needed to remain free of dermatitis. We hypothesize that the agreement rates between the physician and patient relevance assessments will vary based on properties both intrinsic and extrinsic to the allergen in question. We mailed 407 Institutional Review Board-approved questionnaires to patients and analyzed results for the 92 patients reporting greater than 80% improvement of their dermatitis. Cross-reacting allergens tested on the same patient were combined for analysis. Percent agreement was used to assess interrater concordance. Percent agreement regarding relevance for each allergen or group of allergens was as follows: formaldehyde and formaldehyde-releasing preservatives, 88%; neomycin sulfate, 78%; nickel sulfate hexahydrate, 71%; fragrance mix and related products, 65%; and gold sodium thiosulfate, 56%. Relevance varies between allergens. Physician assessment of relevance at the time of final reading is not the ideal method for determining allergen relevance. This has implications for when best to determine the relevance of certain allergens. For allergens with lower agreement, in particular, extended follow-up is recommended to accurately determine an allergen's contribution to a patient's allergic contact dermatitis, especially in those circumstances in which a patient's condition has not improved.

Positive concomitant test reactions to allergens in the standard patch test series

Patch testing is performed to evaluate suspected allergic contact dermatitis. Common wisdom suggests that various allergens cross-react but only a few larger studies have published confirmations of this. The purpose of our study was to identify significant correlations between positive test reactions in a screening series. A total of 1235 patients undergoing patch testing to the Hermal standard series at the Massachusetts General Hospital, Contact Dermatitis Clinic between 1990 and 2006 were investigated. Two or more positive reactions were seen in 411 patients (33.3%). Sensitizations to eight pairs of allergens were found to have significant correlation (P <or= 0.0001). A strong association was observed for cross reactions between formaldehyde and its releasers quaternium 15 and imidazolidinyl urea and between balsam of Peru and fragrance mix. Moreover, significant co-sensitization was identified for potassium dichromate and colophony. Three significant pairings in our study were associations between fragrances and metals. Our data confirm the previously published cross-reactions in the literature between fragrance components, and formaldehyde and formaldehyde-releasing preservatives. The increased numbers of patients with metal and fragrance sensitization can be considered as a random finding due to independent sensitization. Being aware of cross-reacting allergens is essential to success in resolving allergic dermatitis when counseling patients.

Sodium Hydroxymethylglycinate

Sodium hydroxymethylglycinate (SHMG) is a preservative used in many commercially available products, including shampoos, conditioners, soaps, moisturizers, body sprays, baby wipes, room sprays, cleaning agents, and pesticides. It is in a class of chemicals known as formaldehyde-releasing preservatives. Notably, members of this class have been associated with allergic contact dermatitis, possibly due to the agents themselves, the formaldehyde they release, or both. Studies on SHMG in animals have demonstrated potential for sensitization and dermatitis, and formaldehyde-allergic patients have been reported to improve when products containing SHMG are avoided. Patients and providers need to be aware of this preservative.

Concomitant contact allergy to methylchloroisothiazolinone/�methylisothiazolinone and formaldehyde-releasing preservatives

Concomitant contact allergy to methylchloroisothiazolinone/�methylisothiazolinone and formaldehyde-releasing preservatives

Sodium Hydroxymethylglycinate: A Potentia Formaldehyde-Releasing Preservative in Child Products

Sodium Hydroxymethylglycinate: A Potentia Formaldehyde-Releasing Preservative in Child Products

Formaldehyde-Releasing Preservative in Baby and Cosmetic Products

Formaldehyde-Releasing Preservative in Baby and Cosmetic Products

A novel derivatization-free method of formaldehyde and propylene glycol determination in hydrogels by liquid chromatography with refractometric detection

The paper describes the development and validation of a new derivatization-free liquid chromatography method for simultaneous determination of propylene glycol and formaldehyde in the formulations containing formaldehyde-releasing preservative. Highly swollen hydrogel made of poly(ethylene glycol)-protein conjugates was taken as a model formulation for integration of the propylene glycol and the diazolydinyl urea as formaldehyde releaser. The method is shown to be simple and selective and, more importantly, allows determining an existing level of formaldehyde at the moment of analysis instead of all available formaldehyde that might be released during chemical derivatization. After liquid extraction the propylene glycol (PG) and formaldehyde (FA) amounts are determined chromatographically on a Shodex SH 1011 ligand-exchange column using 0.01M sulfuric acid mobile phase, a flow rate of 1.0ml/min and RI detection. The assay is validated showing good linearity, precision, and accuracy. The limits of detection of formaldehyde and propylene glycol in the analyzed solutions were estimated to be 25ng and 87ng, respectively. This analytical assay is considered useful for product stability studies and in developing new formaldehyde releaser-containing formulations where the concentration of formaldehyde is a presumable subject of labeling requirements. This method can also provide a rapid and convenient alternative to gas chromatography method of propylene glycol quantification.

Occupational contact allergy to formaldehyde and formaldehyde releasers

Formaldehyde allergy is common and usually derives from formaldehyde-releasing biocides in cosmetic and other products. To analyse patterns of patch test reactions to formaldehyde and formaldehyde-releasing compounds and the sources of sensitization. At the Finnish Institute of Occupational Health, we screened the patch test files for allergic reactions to formaldehyde and 12 formaldehyde-releasing compounds. All patients with contact allergy to any of the substances were included, and their records were reviewed. Between January 2001 and May 2007, we had patch tested 81 patients with formaldehyde allergy and 18 with independent allergy to some formaldehyde releaser. Of the formaldehyde allergies, 60 were new sensitizations, 25 of which were considered to be occupational. The most common source of occupational sensitization was metalworking fluids followed by creams and related products. Exposure to formaldehyde-releasing preservatives in liquid soaps and other rinse-off products was common in both occupational and non-occupational cases. Reactions to formaldehyde-releasing compounds were seen in 79% of the formaldehyde-allergic patients. Occupational formaldehyde allergy was common and occurred in metalworkers, hairdressers, masseurs, and workers using protective creams, detergents, and liquid soaps. When compared with studies on general dermatological patients, contact allergy to formaldehyde releasers without formaldehyde allergy was rare.

Allergens in Corticosteroid Vehicles

Whereas allergy to vehicle ingredients (ie, excipients and preservatives) in topical steroid vehicles is well recognized, there are no data regarding which vehicle ingredients are in common use or on which vehicles and active molecules are associated with which ingredients. To produce descriptive data on the use of allergenic vehicle ingredients in prescription topical corticosteroids. The package insert for every steroid in widespread use in the United States was obtained from the manufacturer and used to generate an ingredient list for the product. There are seven vehicle ingredients that are commonly used in topical corticosteroid vehicles that are well-known allergens: propylene glycol, sorbitan sesquioleate, formaldehyde-releasing preservatives, parabens, methylchloroisothiazolinone/methylisothiazolinone, lanolin, and fragrance. Of 166 topical corticosteroids, 128 (including all creams) had at least one of these vehicle ingredients. More generic products were free of allergens than were branded products. Solutions and ointments were the least allergenic vehicles. The most commonly present potential allergens were propylene glycol and sorbitan sesquioleate. Most prescription topical corticosteroids have the potential to cause allergic contact dermatitis owing to vehicle ingredients. Dermatologists should be aware of this possibility and should consider prescribing agents that do not contain potentially allergenic vehicle ingredients.