Blue Covarine in Toothpaste: A Comprehensive Review and Meta Analysis of Efficacy, Safety, and Potential Effects

ABSTRACT

Background

The pursuit of whiter teeth has led to the innovation of various colour enhancement products, including toothpaste formulations containing blue covarine. This systematic review and meta‐analysis assesses their efficacy and safety.

Objectives

To evaluate the efficacy of blue covarine‐containing toothpaste in colour enhancement and its safety.

Methods

We conducted a comprehensive search of databases such as PubMed, Scholar, Web of Science, and Cochrane Reviews, from inception until march 25, 2023. Eligible studies involved human participants using toothpaste with blue covarine and reported on its efficacy and safety in tooth colour perception altering. the JBI critical appraisal tools were used to assess the risk of bias.

Results

The meta‐analysis synthesised data from several studies that measured tooth colour improvement and perception of tooth colour. Results showed significant improvement in tooth colour and perceived brightness in individuals using blue covarine toothpaste compared to placebo or other methods. Subgroup analyses revealed consistent results across varying study designs, sample sizes, and follow‐up durations. However, limitations such as study heterogeneity and small sample sizes were noted.

Conclusions

Toothpaste containing blue covarine is effective for tooth colour perception altering and can be recommended as a non‐invasive option by dental professionals, taking into account individual baseline tooth colour and oral health. While promising, the long‐term safety and effects of such toothpaste warrant further research. Dental professionals should personalise treatment recommendations and prioritise patient education to optimise outcomes. Future research should focus on long‐term impacts, different formulations, and larger diverse samples to fully elucidate the safety and efficacy profiles.

1. Introduction

Phthalocyanine blue, also referred to as blue covarine, CI 74160, pigment blue 15, or copper phthalocyanine blue, is a synthetic organic pigment utilised in diverse applications [1]. In the medical industry, phthalocyanine blue is used as a colourant in pharmaceutical formulations [2, 3]. In cosmetics, it serves as a pigment in products such as eyeshadows, lipsticks, and nail polishes [4]. Non‐toxicity of phthalocyanine blue ingestion has recently aroused the interest of the Organic Electronics community [5, 6], to employ it as an organic semiconductor [7, 8, 9] for bioelectronic applications, such as edible biosensors for digestive system monitoring [10, 11, 12, 13, 14, 15, 16].

Blue covarine has become an important component in oral hygiene products, especially in toothpastes where it's used in small amounts to provide a blue‐violet hue. This hue counteracts teeth's yellowish tones, creating a visually whiter appearance through colour perception principles. The use of covarine in toothpastes is approved by regulatory bodies like the US Food and Drug Administration (FDA) and the European Union (EU), underscoring its safety and effectiveness [17, 18].

Tooth colour perception altering products enhance dental brightness by altering natural colour or removing extrinsic stains [19]. Colour enhancement toothpastes often use abrasive systems, incorporating agents like peroxide, enzymes, and blue covarine to boost efficacy. Peroxides, hydrogen or carbamide peroxide, diffuse into teeth and bleach coloured components. However, their effectiveness is debated due to low permissible concentrations—typically around 1 wt% in cosmetic toothpastes, with even lower limits like 0.1 wt% in the European Union [20, 21]. While some studies suggest whitening toothpastes mainly work via abrasion [22], others note significant effects from formulas containing about 1% hydrogen peroxide, albeit in vitro [17]. The low peroxide concentrations, brief contact times, and issues with peroxide stability raise questions about their capacity to affect physical changes in enamel [17, 18].

Whitening toothpastes can affect the mineral content of teeth, often increasing surface roughness and reducing microhardness, which might lighten teeth by one or two shades [23]. Given the potential drawbacks of these products, exploring less invasive alternatives is crucial. Inert pigments in toothpastes, like blue covarine, offer a promising solution. These pigments deposit on teeth, altering their optical properties for an immediate colour perception‐altering effect without excessive abrasiveness. Both in vitro and in vivo studies affirm this method's efficacy, highlighting its safety and added benefits such as fluoride provision [18].

Tooth colour enhancement is commonly assessed using the CIELab colour space, which measures colour changes across three components: L* (lightness), a* (red‐green axis), and b* (blue‐yellow axis). This system provides a standardised method for evaluating the efficacy of colour perception‐altering treatments through objective colour measurements [24, 25]. Furthermore, it's crucial to consider the psychosocial and aesthetic perceptions of patients. Thus, the CIELab system not only quantifies the physical changes in tooth colour but also helps in understanding the treatment's overall effect on patient well‐being. Clinical studies highlight the yellow‐blue shift (b*) as key to perceived tooth colour perception alteration [26]. Blue covarine effectively reduces the b* value, suggesting a shift from yellow towards blue, which enhances the optical properties of teeth, making them appear whiter [27]. This alteration in optical qualities is achieved through the deposition of blue covarine on the tooth surface, thus reducing yellowness and improving overall whiteness [28].

This systematic review and meta‐analysis aims to thoroughly assess the use of blue covarine in toothpaste, focusing on its colour perception‐altering efficacy, safety, potential side effects, and other relevant impacts on toothpaste formulations.

2. Material and Method

2.1. Study Design

This study has been conducted as a systematic review and meta‐analysis of the literature. The protocol has been established in accordance with the newly updated PRISMA statement [29]. The study has been registered on the International Prospective Register of Systematic Reviews (PROSPERO) database under the number CRD42023426089. The Joanna Briggs Institute (JBI) Manual has been used to evaluate bias [30]. This systematic review and meta‐analysis follows the guidelines of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) statement. The PRISMA checklist has been completed to ensure comprehensive reporting of this review and is included as Supporting Information.

2.2. Eligibility Criteria

The eligibility criteria for study inclusion in this systematic review were as follows:

• Study Population: Studies involving human participants of any age or gender were included.

• Interventions: Studies evaluating toothpaste formulations containing blue covarine (CL 74610) as an active ingredient for teeth colour perception altering were included.

• Comparators: Studies comparing toothpaste containing blue covarine with placebo toothpaste or other tooth colour perception‐altering methods were included.

• Outcomes: Studies reporting quantitative or qualitative data on the efficacy of toothpaste containing blue covarine were included. Specifically, outcomes of interest included tooth colour perception altering, tooth colour improvement, and perception of whiteness. Studies assessing the safety, potential side effects, or risks associated with the use of toothpaste containing blue covarine were also included.

• Study Design: Randomised controlled trials (RCTs), non‐randomised controlled trials, comparative studies, observational studies, and experimental studies were considered for inclusion.

• Non‐human studies were included for Supporting Information to provide additional context and understanding of the mechanisms behind blue covarine's effects. These studies were not part of the primary analysis but were considered valuable for supporting the clinical findings.

• Setting: Studies conducted in any setting, including clinical or laboratory settings, were included.

• Time Frame: No specific time frame was set to include studies, encompassing both historical and recent publications.

• Report Characteristics: All years up to the present were considered for inclusion. Studies published in English were included. Non‐English studies were considered if an English translation of the full text was available. Both published and unpublished studies, including conference abstracts and grey literature, were considered for inclusion.

To account for potential methodological variations and biases introduced by including a wide range of study designs, we conducted subgroup analyses and sensitivity analyses. These analyses were designed to assess the impact of different study designs on the overall conclusions, ensuring a robust synthesis of the evidence. In vitro and animal studies were included as Supporting Information to support the findings from human clinical studies. These studies were not part of the primary analysis but provided additional context and understanding of the mechanisms behind blue covarine's effects. To address potential variability due to the broad time frame of included studies, a temporal analysis was performed to examine any trends or changes in outcomes over time. This analysis helped to contextualise the findings within the evolving methodologies. Studies assessing blue covarine without a comparator were also eligible if they provided relevant and robust data on the outcomes of interest. This inclusion criterion ensured that all pertinent data were considered.

Exclusion Criteria: Publications of case reports and literature reviews were excluded. Studies solely focused on topics unrelated to dental traits or not specifically related to toothpaste formulations containing blue covarine were excluded.

2.3. Sources of Information and Search Strategy

The search strategy was conducted on March 25, 2023, and included four databases: PubMed, Google Scholar, Web of Science (WOS), and Cochrane Reviews. The key words used for the search were “Covarin” OR “Covarine” OR “Blue Covarin” OR “Blue Covarine” OR “CL74610” AND “toothpaste” OR “dentifrice.” The search terms were applied to the title and abstract fields of the articles. The search strategy aimed to identify relevant studies evaluating the use of toothpaste formulations containing blue covarine for teeth colour perception altering. Relevant conferences in the field of dentistry and oral health were searched for abstracts or proceedings. Relevant government websites, regulatory bodies, and organisations were searched for reports and policy documents related to tooth colour perception altering products.

To broaden the scope of the review, searches were expanded to include non‐English sources with the assistance of a translator, where feasible. This included translating search terms into Spanish, French, German, and Chinese to ensure a comprehensive search across different languages.

Structured data extraction templates were developed to systematically collect relevant information from included studies. These templates were created using spreadsheet software in Microsoft Excel. The forms included predetermined fields to capture key study characteristics, outcomes, and other relevant data points. A secure and centralised location was created for storing all review‐related documents and data. This was achieved through a cloud‐based storage service (Google Drive). Detailed documentation of all review activities, including search strategies, screening processes, data extraction procedures, and any changes or decisions made during the review, was maintained.

2.4. Study Selection

The process of study selection involved several stages and was conducted by two independent reviewers (BP and SK). In the initial stage, duplicate records were removed using reference management software, Rayyan [31]. Subsequently, the reviewers screened the titles and abstracts of the remaining records based on the predefined eligibility criteria. Next, the full texts of potentially eligible articles were obtained and assessed for final inclusion. Any disagreements or discrepancies between the reviewers were resolved through discussion and, if necessary, consultation with a third reviewer (LM). The reviewers carefully evaluated each study based on the predetermined eligibility criteria. The included studies were carefully assessed for their relevance to the research question and the specific objectives of the review. The final selection of studies was documented, and reasons for exclusion were recorded. The process of study selection is illustrated in the PRISMA flow diagram (Figure 1).

FIGURE 1.

Prisma flowchart of the research process.

2.5. Data Collection

During the data collection phase, relevant information was systematically extracted from the full‐text articles that met the inclusion criteria. The extraction process was carried out in a systematic and structured manner to ensure consistency and accuracy. The following data points were extracted from each included study, where available and applicable:

1. Authorship, Year of Publication, and Country: Details about the authors, the year the study was published, and the country in which the study was conducted were recorded.

2. Study Objectives: The main objective of each study was extracted to provide a comprehensive overview.

3. Study Design and Methodology: Detailed information about each study's design (e.g., randomised controlled trial, observational study), duration of the study, and the specific methods used for teeth colour perception altering was extracted.

4. The sample size of each study was evaluated to assess the statistical power and generalizability of the findings. The methodology employed in each study was assessed to determine the rigor and validity of the research design. This included evaluating aspects such as randomization, blinding, allocation concealment, data collection methods, and follow‐up procedures. The overall quality of each study was evaluated based on the assessed characteristics and risk of bias.

5. Participant Demographics: For each study's sample, details on participants' age range, gender distribution, and other pertinent demographic data (e.g., smoking status, previous dental treatments) were collected where available.

6. Inclusion and Exclusion Criteria: Specific inclusion or exclusion criteria employed in each study were documented. These characteristics were important for understanding the applicability and generalizability of the study findings.

7. Outcome Measures: Relevant outcome measures related to the efficacy and safety of toothpaste formulations containing blue covarine were extracted. This encompassed data on tooth colour perception altering, tooth colour improvement, perception of whiteness, and any reported safety outcomes or potential side effects. We also noted the specific measurement scales or tools used by each study to assess outcomes such as tooth colour improvement.

8. Funding Sources: Information on whether the studies were independent or company‐funded was collected to identify potential biases.

9. Other Relevant Data: Additional data points relevant to the study's findings were extracted as needed to provide a thorough analysis.

2.6. Bias Assessment

The Joanna Briggs Institute's (JBI) Critical Appraisal Tools were employed to evaluate the risk of bias in the included studies. Each included study was independently appraised by two reviewers using the appropriate JBI Critical Appraisal Tool for the specific study design. The JBI Critical Appraisal Tools consisted of a series of criteria that covered various aspects of study design, conduct, and reporting. The reviewers assessed each criterion and assigned a judgement of “Yes”, “No”, “Unclear”, or “Not applicable” based on the information provided in the study. The total score was then reported out of 100. Two evaluators (BP, SK) independently assessed each domain of the checklists. The risk of bias was rated as high when the study reached a score of less than 50%, moderate when it reached a score between 50% and 70%, and low when it reached a score of more than 70% [30, 32]. Discrepancies or disagreements between the reviewers' assessments were resolved through discussion and consensus. In cases where consensus could not be reached, a third reviewer (LM) was consulted to make the final decision. For randomised controlled trials (RCTs), criteria such as random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, selective outcome reporting, and other sources of bias were considered. The reviewers carefully examined the relevant sections of each study, including the methods, results, and discussion, to gather the necessary information for the bias assessment. Furthermore, we assessed whether the studies were independent or company‐funded to evaluate potential sources of bias. Studies funded by companies with a vested interest in the outcomes were scrutinised more closely for potential conflicts of interest. Additionally, we considered the impact of the blue colouring of covarine‐containing products on the blinding process. The visibility of the blue colour could potentially unblind participants or assessors, introducing bias. We evaluated the methods used in each study to maintain blinding and noted any instances where the blinding could have been compromised.

The findings and key characteristics of each included study were summarized in a descriptive manner. This involved extracting relevant data from the studies, including study design, participant characteristics, interventions, outcomes, and results.

For the included studies deemed appropriate for quantitative synthesis and with sufficient homogeneity in terms of study design, interventions, and outcome measures, a meta‐analysis was conducted. The specific models were used depending on the type of outcome measures and the available data:

1. Effect Size Calculation: For each outcome of interest, the appropriate effect size measure (such as risk ratios, odds ratios, or mean differences) was calculated based on the available data from individual studies.

2. Statistical Heterogeneity: Statistical heterogeneity among the included studies was assessed using measures such as the Cochran's Q‐test and the I ² statistic. In cases where substantial heterogeneity was present, possible sources of heterogeneity were explored.

3. Forest Plots: The results of the meta‐analysis were presented using forest plots, displaying the effect sizes and confidence intervals for each study, as well as the overall pooled estimate. Statistical analysis and meta‐analysis were conducted using GraphPad Prism software package and RevMan (Review Manager) software.

The narrative summaries involved systematically summarizing and presenting the relevant information from each included study, highlighting study characteristics, interventions, outcomes assessed, and the reported findings. The narrative summaries were designed with the goal of offering a thorough synopsis of the outcomes of each individual study, encompassing any divergences or contradictions in findings among the various studies. In order to aid in the composing procedure, a language model known as ChatGPT, created by the organization OpenAI, was utilized. ChatGPT was deployed for the purpose of crafting sentences.

3. Results

3.1. Study Selection

A total of 427 references were obtained through research conducted on four databases (PubMed, Scholar, Web of Science, Cochrane Reviews), as well as grey literature. Following the removal of duplicates, a careful examination of titles and abstracts was performed on 273 articles. Among these, 249 were excluded as they did not align with the objective of the review and meta‐analysis, resulting in 24 articles selected for a comprehensive assessment of their eligibility criteria. Subsequently, upon a thorough reading of the full texts, an additional 19 articles were excluded due to their lack of human participants and inadequate methodology for the purpose of this review. Eventually, a total of 5 articles were included that fully met the eligibility criteria for systematic review and meta‐analysis (see Figure 1).

3.2. Characteristics of the Selected Studies

Selected articles assessed in the full text were published from 2009 to 2022. There were 3 randomised clinical trials [33, 34, 35, 36], 2 cross‐sectional clinical studies [37, 38] and 19 studies performed on various clinical samples, but without human participants [27, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56]. Notably, the study by Collins et al. [37] was supported by Unilever Oral Care, while the other four studies involving human participants [33, 34, 35, 38] were conducted without any connections to companies manufacturing toothpastes. The majority of the studies performed on extracted teeth evaluated the efficacy of blue covarine toothpaste for tooth colour perception‐altering procedures on intact [40, 43, 45, 47], stained [46] enamel and bovine teeth [29, 41, 43, 49, 54]. The study performed by Jiang et al. showed that the use of a colour perception‐altering toothpaste containing blue covarine during in‐office bleaching resulted in the lowest colour changes compared to other groups. On the other hand Collins and his coworkers reported that brushing with a silica colour perception‐altering toothpaste containing blue covarine led to a significant reduction in tooth yellowness and improvement in tooth whiteness immediately after brushing [37]. In line with that there is a report showing that toothpastes containing blue covarine demonstrated a significant reduction in tooth yellowness and improvement in tooth whiteness immediately after brushing [44]. All of these studies used CIELAB parameters, L*, a* and b*, for the objectivization of the colour perception‐altering effect. Finally, Joiner et al. claimed that the new silica‐based colour perception‐altering toothpaste containing blue covarine is effective in removing extrinsic stains, is not excessively abrasive to enamel and dentine, and provides an efficacious source of fluoride [47].

Significant amounts of studies focused on comparison with conventional bleaching techniques. Dantas et al. find no significant differences in colour perception altering efficacy between the blue covarine toothpaste, a standard whitening toothpaste, and a control, but neither of the toothpastes tested demonstrated the same level of effectiveness as in‐office or at‐home bleaching treatments [39]. The study conducted by Bartolato et al. aimed to investigate different aspects of the covarine containing toothpaste and their results suggest that toothpastes containing blue covarine do not produce additional colour alteration on teeth that have already undergone bleaching with conventional techniques [41]. There were also reports indicating that toothpastes containing blue covarine and microbead abrasives showed the best tooth colour perception altering performance after initial use, and blue covarine exhibited the greatest colour perception altering performance after continuous use [43].

One group of studies focused on the effects of covarine‐containing toothpaste on enamel and restorative materials. The study conducted by Andrade and coworkers shows that whitening toothpaste caused significant colour changes and increased surface roughness of dental enamel but had no deleterious effects on the microhardness of dental enamel [40]. On the other hand there are reports suggesting that the silica colour perception‐altering toothpaste containing blue covarine did not cause significant staining on anterior restoration materials [48]. Also, the study performed by Odilon et al. found that toothpastes containing blue covarine did not cause significant alterations in the roughness and mass of bovine enamel [49].

Some studies compared the effect of covarine with the effects of activated charcoal. Aydin et al. reported that activated charcoal‐containing toothpaste had the greatest colour perception altering effect after 7, 14, and 28 days of use [53]. It is worth noticing that in one comparative study, it has been reported that toothpastes containing activated charcoal are abrasive to dental tissues, causing enamel wear and potentially leading to tooth hypersensitivity [55].

Colour perception‐altering effects on different dental materials have been investigated in the study reported by Oliveira et al. that demonstrated that both the blue covarine toothpaste and control toothpaste were effective in reducing dental staining caused by different coloured beverages [51]. In line with that Philipotss et al. found that the silica‐based blue covarine toothpaste did not cause significant staining on tested restorative dental materials [50].

3.3. Identification of Bias in Studies

Tables 1 and 2 show that all 5 studies (3 randomised clinical trials and 2 cross sectional clinical studies) fulfilled all the criteria from the JBI Critical Appraisal Tools checklists [30, 32] and rated a low risk of bias.

TABLE 1.

Randomised clinical trials' risks of bias assessed by checklist for Qualitative Research from Joanna Briggs Institute's (JBI) Critical Appraisal Tools [32].

Author	Was true randomization used for assignment of participants to treatment groups?	Was allocation to treatment groups concealed	Were treatment groups similar at the baseline?	Were participants blind to treatment assignment?	Were those delivering the treatment blind to treatment assignment?	Were treatment groups treated identically other than the intervention of interest?	Were outcome assessors blind to treatment assignment?	Were outcomes measured in the same way for treatment groups?	Were outcomes measured in a reliable way	Was follow up complete and if not, were differences between groups in terms of their follow up adequately described and analysed?	Were participants analysed in the groups to which they were randomised?	Was appropriate statistical analysis used?	Was the trial design appropriate and any deviations from the standard RCT design (individual randomization, parallel groups) accounted for in the conduct and analysis of the trial?	Total	%
Meireles [33]	1	1	1	1	1	1	1	1	1	1	1	1	0.5	12.5	96
Jiang [34]	1	1	1	1	1	1	1	1	1	1	1	1	1	13	100
Schlafer [35]	1	1	1	1	1	1	1	1	1	1	1	1	1	13	100

Abbreviations: 0, no; 0.5, unclear; 1, yes; NA, not applicable.

TABLE 2.

Cross sectional studies' risks of bias assessed by checklist for Cross Sectional Studies from Joanna Briggs Institute's (JBI) Critical Appraisal Tools [30].

Author	1. Were the criteria for inclusion in the sample clearly defined?	2. Were the study subjects and the setting described in detail?	3. Was the exposure measured in a valid and reliable way?	4. Were objective, standard criteria used for measurement of	5. Were confounding factors identified?	6. Were strategies to deal with confounding factors stated?	7. Were the outcomes measured in a valid and reliable way?	8. Was appropriate statistical analysis used?	Total	%
Collins [37]	1	1	1	1	0	0	1	1	6	75
Porciani [38]	1	1	1	1	0	0	1	1	6	75

Abbreviations: 0, no; 0.5, unclear; 1, yes; NA, not applicable.

3.4. Results of Individual Studies

Qualitative data from all included studies are detailed in Table 3. Quantitative analysis of the results from the same studies has also been performed and the results are shown in Tables 4 and 5 and Figures 2 and 3.

TABLE 3.

Summary of findings from clinical studies.

Study	Study design	Sample size	Research objective	Additional variables	Key findings
Meireles [33]	RCT	75	Evaluation of the efficacy and safety of a blue‐covarine whitening toothpaste on tooth bleaching	Subjects' perception about improvement on tooth appearance Tooth sensitivity and gingival irritation Acceptability	No significant differences were observed in tooth shade or colour parameters between the WT group and other treatment groups. WT showed a decrease in b* values after the first application and at 2 weeks compared to baseline. WT exhibited no significant differences in colour change values compared to the conventional toothpaste (CT) group over time. Subjects using WT reported mild improvement in tooth appearance, with a satisfaction level similar to the CT group. Tooth sensitivity and gingival irritation were less frequently reported by subjects in the WT group compared to the group using the product containing 10% carbamide peroxide (CP10)
Jiang [34]	RCT	20	To determine whether whitening dentifrices would improve the effectiveness of inoffice tooth bleaching procedures	Sensitivity	Group CU, no significant adverse reactions during the treatment period. Group CU showed significant tooth whitening effects, with increased L* and W values and decreased a* and b* values. Group CU had significantly lower colour change values compared to the other groups. At the end of the bleaching treatment, Group CU showed an increase in colour change values (DE) compared to the previous assessment
Schlafer [35]	RCT	24	To evaluate whether a blue covarine containing silica‐based toothpaste promotes a whitening effect immediately after tooth brushing	Participants' satisfaction with tooth colour	There were no statistically significant changes in colour measurements or participants' perception and satisfaction. No significant differences were observed for changes in colour components or dimensions, as well as L*, a*, and b* values of the CIELAB colour space for either treatment. Participants' satisfaction with tooth colour did not significantly differ between the two treatment groups
Collins [37]	Controlled, single blind, cross‐over study	78	To measure the whitening effect delivered after brushing with a silica whitening toothpaste containing blue covarine	/	Toothpaste containing blue covarine significantly whitened teeth as indicated by the DWIO whiteness index. The test toothpaste with blue covarine resulted in a statistically significant reduction in tooth yellowness. The whitening toothpaste with blue covarine was significantly more effective in reducing tooth yellowness and redness
Porciani [38]	Single‐blind, parallel trial	424	Evaluate the whitening effect of two chewing gums and one denti frice	Acceptance and sensitivity	The whitening tools (whitening chewing gums and dentifrice) showed statistically significant increases in WIO and WID compared to the placebo chewing gum, but no significant differences were found among the three whitening tools

TABLE 4.

Meta‐analysis results: changes in L*, a*, and b* values and heterogeneity measures in the included RCT.

Author	L* (Δ)	L* (SD)	95% CI	Cohen's d	a* (Δ)	a* (SD)	b* (DΔ)	Cohen's d	95% CI	b* (SD)	95% CI	Cohen's d	Sample size
Meireles et al. [33]	−0.6	0.5	−1.6 to −0.4	−1.2	−0.1	0.4	−0.4	−0.25	−0.8 to 0.6	0.5	−1.4 to 0.6	−0.8	75
Jiang et al. [34]	2.72	0.66	1.39–4.05	4.12	−0.49	0.57	−6.40	−0.86	−1.63 to 0.65	0.88	−8.17 to 4.63	−7.27	20
Schlafer et al. [35]	−0.7	1.2	−3.0 to 1.6	−0.58	−0.6	0.6	−5.3	−1.0	−1.8 to 0.6	3.20	−11.7 to 1.1	−1.66	24
Heterogeneity	p = 0.284.				p = 0.037					p = 0.014
Tau2	0.093				0.002					0.009
Chi2	1.019				6.215					8.933
Df	2				2					2
P	0.600				0.045					0.011
I 2	0.00000%				75.000%					77.133%
Z	0.162				0.971					−2.993
p	0.871				0.332					0.003

TABLE 5.

Meta‐analysis results: Changes in L*, a*, and b* values and heterogeneity measures in the included cross‐sectional clinical studies.

Author	L* (Delta) Mean	L* (SD)	95% CI	Cohen's d	a* (Delta) mean	a* (SD)	95% CI	Cohen's d	b* (Delta) mean	b* (SD)	95% CI	Cohen's d	Sample size
Collins [37]	0.20	0.11	0.155–0.245	1.818	0.21	0.03	0.197–0.223	0.204	−0.36	0.06	−0.387 to −0.333	−5.682	78
Porciani [38]	0.24	1.87	−0.016 to 0.496	0.128	−0.07	0.68	−0.123 to −0.017	−0.103	−0.37	1.24	−0.486 to −0.254	−0.258	424
Heterogeneity	p = 0.60				p = 0.45				p = 0.011
Tau2	0.01395				0.00018				0.0017
Chi2	245.213				690.129				1839.055
Df	1				1				1
p	0.0000001				< 0.000001				< 0.000001
I 2	99.593				99.856%				99.946%
Z	25.258				10.891				−21.279
p	< 0.000001				< 0.000001				< 0.000001

FIGURE 2.

Forest plot: meta‐analysis results of changes in L*, a*, and b* values in studies by Meireles et al. [33]., Jiang et al. [34], and Schlafer et al. [35].

FIGURE 3.

Forest plot: meta‐analysis results of changes in L*, a*, and b* values in studies by Collins et al. [37] and Porciani et al. [38].

In Meireles et al. [33], there was a decrease in L* and b* values, while the a* value showed a minimal change. They reported a decrease of −0.6 in L* value, indicating a slight reduction in lightness after the intervention. The minimal change of −0.1 in the a* value suggests a negligible shift in the red‐green axis. Additionally, a decrease of −0.4 in the b* value was observed, indicating a minor change in the yellow‐blue axis. Jiang et al. [34] reported an increase of 2.72 in L* value, suggesting a notable improvement in tooth lightness. They also observed a decrease of −0.49 in the a* value, indicating a slight shift towards the green axis. Furthermore, a substantial decrease of −6.40 in the b* value was reported, indicating a significant reduction in the yellow‐blue axis. Schlafer et al. found a decrease of −0.7 in L* value, indicating a minor decrease in tooth lightness. They also reported a slight decrease of −0.6 in the a* value, suggesting a minimal shift towards the green axis. Furthermore, they observed a substantial decrease of −5.3 in the b* value, indicating a significant reduction in the yellow‐blue axis. The analysis of colour parameters (L*, a*, b*) revealed significant heterogeneity in the a* and b* dimensions (p = 0.037 and p = 0.014, respectively), indicating variations in tooth colour outcomes among the studies. Overall, the meta‐analysis showed a significant effect of covarine containing toothpaste formulation on the b* parameter (p = 0.003), indicating a clinically relevant impact on tooth colour. However, no significant effects were found for the L* (p = 0.871) and a* (p = 0.332) parameters. The I ² statistics indicated low heterogeneity for the L parameter (0.00%) and moderate‐to‐high heterogeneity for the a (75.00%) and b (77.133%) parameters. The test for overall effect confirmed a significant association between toothpaste formulation and tooth colour (Z = −2.993, p = 0.011). These findings suggest that covarine containing toothpaste plays a role in altering tooth colour, particularly in the b* dimension.

In the study by Collins et al. [37], there was a significant increase of 0.20 in ΔL* value, indicating a lightening effect on tooth colour. Similarly, there was a significant increase of 0.21 in Δa* value, suggesting a shift towards redness. However, there was a non‐significant decrease of −0.36 in Δb* value, indicating a minimal change in yellowness.

In the study conducted by Porciani et al. [38], a relatively larger sample size of 424 participants was included. The results showed a non‐significant increase of 0.24 in ΔL* value, suggesting a slight improvement in tooth colour. There was a significant decrease of −0.07 in Δa* value, indicating a shift towards greenness. Additionally, there was a significant decrease of −0.37 in Δb* value, suggesting a reduction in yellowness. In summary, the meta‐analysis results demonstrate significant effects for the parameters L* and b* in both the Collins et al. [37], and Porciani et al. [38] studies. However, the parameter a* shows a significant effect only in the Collins study [37]. Heterogeneity is observed in all three parameters, suggesting variations across the studies.

Quantitative data related to the patients' satisfaction with aesthetic improvement were pooled from the studies that investigated these parameters as secondary outcomes. In the study by Meireles et al. [33], it has been reported that subjects using covarine colour perception altering toothpaste reported mild improvement in tooth appearance, with a satisfaction level similar to the control group. Tooth sensitivity and gingival irritation were less frequently reported by subjects in the covarine group compared to the group using a product containing carbamide peroxide. Similarly, in the study by Jiang et al. [34] the experimental group showed no significant adverse reactions during the treatment period. In the Schlafer et al. [35] study, participants' satisfaction with tooth colour using the aesthetic numeric analogue (ANA) scale was measured. The baseline satisfaction level was found to be 6.1 (95% confidence interval: 5.3, 7.0). After the treatment with the toothpaste containing blue covarine, the satisfaction level increased to 6.8 (95% confidence interval: 5.7, 7.8). It is important to note that the p‐value for the comparison before and after treatment is 0.08. This indicates a relatively weak statistical significance, suggesting that the observed increase in satisfaction may not be entirely attributed to the treatment. In the study by Meireles et al. [33], from the given data, we can see that the group using blue covarine toothpaste had very low levels of tooth sensitivity throughout the treatment period (Weeks 1–3), with means of 0.0 and proportions ranging from 4% to 8%. These values suggest that the colour perception altering toothpaste was associated with minimal tooth sensitivity in the study population.

4. Discussion

The growing interest and demand for tooth colour perception altering procedures highlight the need for effective and safe approaches in achieving a brighter smile. Toothpastes have emerged as a popular choice due to their chemical, physical, optical, and enzymatic effects. However, finding a single approach that offers optimal tooth colour perception altering without potential side effects and limitations remains a challenge. For instance, the concentration of peroxide is often limited to mitigate possible adverse reactions. Additionally, concerns arise regarding the increased presence of abrasive materials, which can impact the physical properties of enamel. Therefore, a critical evaluation, understanding, and explanation of each approach are warranted [55, 57]. In recent years, there has been growing interest in a relatively new approach to tooth colour perception altering offered by covarine [28, 42]. Therefore, in this review, we aimed to provide a comprehensive overview of the covarine‐based tooth colour perception altering, emphasising the importance of understanding its mechanisms of action and potential implications.

While it is true that the majority of the available data on covarine toothpaste is derived from in vitro studies [39, 42, 44], it is important to highlight that this review specifically focuses on the clinical effects of covarine‐containing toothpaste. In this review, we included non‐human studies to supplement the clinical data by providing insights into the colour‐changing effects on natural teeth. While these studies do not directly involve human participants, they offer valuable information on the mechanisms and potential efficacy of blue covarine in dental applications. This approach allows us to present a more comprehensive overview of the existing evidence, highlighting both clinical and supplementary findings. By narrowing the scope of the review to clinical studies, we are addressing the need for evidence‐based assessments of the real effects of covarine toothpaste on tooth colour perception altering. While in vitro studies provide valuable insights into the potential mechanisms and efficacy of colour perception altering agents, clinical studies offer a more direct evaluation of the actual effects of covarine toothpaste in human subjects. These studies take into account factors such as oral hygiene practices, saliva flow, and the dynamic environment of the oral cavity, which can influence the performance of toothpaste formulations. By emphasising the clinical aspect of this review, the goal of this review and meta‐analysis was to highlight the practical relevance of available findings and their implications for patients seeking tooth colour perception altering solutions. It is essential to bridge the gap between in vitro research and real‐world outcomes, and this review aims to provide valuable insights into the efficacy and safety of covarine toothpaste in a clinical setting.

The findings from this review highlight the variability in the effects of the interventions on tooth colour. The effect on colour is confirmed in the in vitro studies using different substrates, but these variations are rather specific for the available clinical data. Meireles et al. reported a decrease in the L* value with a small effect size, indicating some colour perception‐altering effect [33]. The b* value also showed a decrease with a moderate effect size, suggesting a change in tooth colour. Jiang et al. found an increase in the L* value with a large effect size, indicating significant colour perception altering [34]. The b* value showed a significant decrease, further supporting tooth colour improvement. Schlafer et al. reported a decrease in the L* value with a small effect size, indicating a mild colour perception‐altering effect [35]. The b* value showed a decrease with a moderate effect size, suggesting a change in tooth colour. However, it is important to note that there was significant heterogeneity among the studies, suggesting variations in the outcomes across different populations and study designs. These findings highlight the potential efficacy of toothpaste formulations containing blue covarine for teeth colour perception altering, but also underscore the need for further research to better understand the underlying mechanisms and optimise the formulation. Future studies should consider standardised protocols and larger sample sizes to improve the robustness of the findings. While Collins' study [37] demonstrated a significant improvement in lightness and redness, Porciani's study showed more inconsistent results with minimal changes in ΔL* and significant shifts in both Δa* and Δb* values [38]. The differences in sample sizes may also contribute to the observed variations. These results emphasise the importance of considering multiple studies in the meta‐analysis to obtain a comprehensive understanding of the overall trends and effects of the interventions on tooth colour.

Although there are significant variations among the studies included in the systematic review and meta‐analysis regarding the effect on tooth colour, they do share some common observations. In all studies, it is noticeable that there were no reported adverse effects, irritations, or any other side effects that could be attributed to the use of toothpaste containing covarine [33, 35]. Additionally, none of the studies has demonstrated that patients were more satisfied with any other alternative or control treatment in terms of participants' satisfaction with tooth colour change. However, it is important to consider these results in the context of the study's limitations and the overall body of evidence from other studies.

Our findings regarding the efficacy of toothpaste formulations containing blue covarine for teeth colour perception altering are consistent with previous research in the field. In terms of safety, our review included studies that assessed potential side effects and risks associated with the use of toothpaste containing blue covarine. None of the included studies reported any adverse effects related to the use of blue covarine toothpaste, suggesting its relative safety for tooth colour perception altering purposes [33, 34]. This finding aligns with the studies conducted by Schlafer et al., which also reported no adverse events associated with the use of blue covarine‐containing toothpaste [35]. It is important to note that the studies included in our review varied in sample sizes, study designs, and outcome measures, which may contribute to heterogeneity in the results. Additionally, the use of different toothpaste formulations and application protocols across studies may introduce variability in the findings. Overall, our review and meta‐analysis contribute to the growing body of evidence supporting the efficacy and safety of toothpaste formulations containing blue covarine for teeth colour perception altering. However, further well‐designed randomised controlled trials with standardised protocols are needed to confirm these findings and establish more precise estimates of effect sizes.

The potential impact of study funding on outcomes was considered. The study by Collins et al. [37] was supported by Unilever Oral Care. In contrast, the other four studies involving human participants [33, 34, 35, 38] were independent of any toothpaste manufacturing companies, which helps to mitigate concerns about commercial bias in these studies. This distinction is crucial for interpreting the results, as company‐funded studies may have inherent biases towards positive outcomes. Additionally, we acknowledge that the blue colouring of covarine‐containing products presents a potential risk for unblinding participants or assessors. The inherent visibility of the blue colour could compromise blinding in clinical assessments. This limitation is recognised as a factor that could introduce bias into the study results, and it is important to consider this when interpreting the findings.

It is important to point to some strengths and main limitations of the present study. The review employed a comprehensive search strategy across multiple databases and included both published and unpublished studies. This approach enhances the likelihood of capturing relevant studies and minimizing publication bias. The review included a range of study designs, such as randomized controlled trials, non‐randomized controlled trials, comparative studies, and observational studies. This allows for a broader examination of the topic and inclusion of diverse evidence. In addition, the review utilized the Joanna Briggs Institute's (JBI) Critical Appraisal Tools to assess the quality and risk of bias of the included studies. This systematic approach enhances the rigor and reliability of the review's findings. Also, the review conducted a meta‐analysis to quantitatively synthesize the data from the included studies. The review assessed heterogeneity among the included studies using appropriate statistical methods. This allows for the identification of variations in the study results and helps to determine the overall consistency and generalizability of the findings.

There were some limitations and drawbacks of the present review and meta‐analysis. Despite efforts to include unpublished studies and grey literature, there is still a possibility of publication bias. Studies with positive or statistically significant results are more likely to be published, while those with negative or non‐significant findings may remain unpublished, leading to a potential bias in the synthesised results. The included studies employed different methodologies to some extent, interventions, and outcome measures, which can introduce heterogeneity and limit the comparability of the results. This heterogeneity should be taken into account when interpreting the findings. The review may have identified a limited number of eligible studies, particularly having in mind that the topic is relatively new. A small sample size can affect the statistical power and generalizability of the results. The quality of the included studies can vary, which may introduce bias or affect the reliability of the findings. The review attempted to mitigate this by using the JBI Critical Appraisal Tools, but inherent limitations of the individual studies cannot be completely eliminated. This review also may not have accounted for all potential confounding factors that could influence the outcomes of the included studies. Factors such as participant characteristics, variations in toothpaste formulations, and compliance with the interventions could impact the results.

The findings suggest that toothpaste formulations containing blue covarine have shown promising results in terms of tooth colour perception altering and colour improvement. This information can be valuable for dental professionals and individuals seeking tooth colour perception altering options. Dentists may consider recommending toothpaste with blue covarine as a non‐invasive and convenient option for patients looking to enhance their tooth colour. While toothpaste containing blue covarine has demonstrated overall efficacy, it is important to consider individual factors such as baseline tooth colour, oral health status, and personal preferences. In our review, while covarine toothpaste formulations have shown promising immediate results in improving tooth colour and perceived whiteness, it is important to note that these effects are temporary. The optical changes induced by covarine are due to its deposition on the tooth surface, which can be removed through regular oral hygiene practices, thereby limiting its long‐term efficacy. This contrasts with peroxide‐based treatments, which chemically alter the intrinsic colour of the teeth, providing more durable whitening effects. Consequently, patients seeking long‐lasting results may find covarine formulations less satisfactory. For instance, studies by Meireles et al. [33] and Jiang et al. [34] indicate that while immediate improvements were observed, the perceived whitening effect diminished over time without continued use of the product. Given these considerations, dental professionals should clearly communicate the temporary nature of covarine's effects and set realistic expectations for patients considering it as a whitening option. Educating patients about the need for ongoing use and potential for diminished effects can help mitigate dissatisfaction. Dental professionals should assess each patient's unique needs and provide personalised recommendations for toothpaste selection and usage. Although the focus of this review was primarily on the efficacy of toothpaste containing blue covarine, it is crucial to consider the safety profile and potential side effects. Future studies should explore the long‐term effects and any adverse reactions associated with the use of these toothpaste formulations. Dental professionals should stay informed about the latest research and guidelines regarding the safety and potential risks of tooth colour perception altering products. While the results of this review provide valuable insights, further research is needed to strengthen the evidence base. Future studies should explore the long‐term effects, compare different formulations and concentrations of toothpaste containing blue covarine, and investigate the impact on different patient populations. Additionally, studies focusing on potential side effects, cost‐effectiveness, and patient satisfaction can further inform clinical practice.

5. Conclusion

This systematic review and meta‐analysis provide evidence supporting the efficacy of toothpaste formulations containing blue covarine in improving tooth colour and perception of whiteness. The findings indicate that blue covarine toothpaste is a non‐invasive and convenient option for tooth colour perception altering. However, limitations such as study heterogeneity and small sample sizes should be considered when interpreting the results. Long‐term safety and potential side effects of blue covarine toothpaste require further investigation. Dental professionals should consider individual factors, such as baseline tooth colour and oral health status, when recommending these products. Future research should focus on exploring the long‐term effects, comparing different formulations and concentrations, and investigating the safety profile in larger and more diverse populations.

6. Clinical Relevance

6.1. Scientific Rationale for Study

Blue covarine toothpaste aims to enhance tooth brightness through color perception alteration.

6.2. Principal Findings

Our review indicates significant tooth colour improvement and perceived whiteness in users of blue covarine toothpaste compared to other methods, despite study heterogeneity and small sample sizes.

6.3. Practical Implications

Blue covarine toothpaste can be recommended by dental professionals as a non‐invasive, immediate colour perception altering option. Individual factors like baseline tooth color and oral health status should be considered. Further research is needed on long‐term safety and potential side effects.

Funding

This research was supported by the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska‐Curie grant agreement No. 872370, and by the European Union Horizon Europe research and innovation program within the project “EINSTEIN”, grant agreement no. 101136377.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.