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The SCCP opinion states:
3.3.11. Human Data
Toothpastes and mouth-rinses
Most of the information below is from the Opinion on hydrogen peroxide and hydrogen peroxide releasing substances used in oral care products (SCCNFP/0158/99).
3.3.11.1 Rate of degradation
Two in vitro studies have shown that hydrogen peroxide in toothpaste formulations is rapidly decomposed in human saliva. In each study, saliva samples were collected from 12 adult subjects. In one study (Sharma [Report], 1996) the saliva was mixed with 1.5 g of a 3% hydrogen peroxide gel (1:1 slurry in water) and the test paste (formulated with baking soda). In the other study (Marshall and Gragg [Report], 1997) toothpastes were prepared that contained 3% hydrogen peroxide and 1100 ppm fluoride from either sodium fluoride or monofluoro-phosphate or stannous fluoride. In both studies the released oxygen was captured and quantified. The majority of the hydrogen peroxide was converted to oxygen in 5 minutes (Sharma [Report], 1996; Marshall and Gragg [Report], 1997).
These findings have been confirmed in vivo in the oral cavity of healthy adult humans. Twelve subjects brushed their teeth with 1 g of a toothpaste gel phase containing 0.3% hydrogen peroxide or 3% hydrogen peroxide and 1100 ppm fluoride from sodium fluoride (30.25 mg hydrogen peroxide delivered). The saliva was collected immediately after brushing and 30, 60, 180, 360 and 540 seconds after brushing. The samples were analysed for hydrogen peroxide content. For the 3% hydrogen peroxide treatment, 70% of the delivered peroxide decomposed during brushing. Both in the absence and presence of fluoride, less than 20% of the administered hydrogen peroxide remained after 1 minute. The authors concluded that fluoride does not interfere with the degradation of hydrogen peroxide (Marshall and Gragg [Report], 1997).
Since fluoride salts are common ingredients in dental products consideration has been given to their potential to inhibit the degradation of hydrogen peroxide in the oral cavity. The effect of sodium fluoride (NaF), sodium monofluorophosphate (MFP) and stannous fluoride (SnF2) on the rate of decomposition of 3% H2O2 was tested in vitro at 37oC with human saliva by monitoring the release of oxygen gas. The profiles of oxygen release in the presence of the fluoride salts did not differ from the profile for 3% H2O2 alone (Marshall and Gragg [Report], 1997).
Marshall et al. (2001) determined the clearance of peroxide from the oral cavity after 1 minute brushing with a 3% hydrogen peroxide dentifrice. Seventy percent of the hydrogen peroxide decomposed during the minute of brushing for infants (3-4 years), juveniles (7-12 years), adults with normal salivary flow and adults with diminished salivary flow (Sjorgren’s syndrome).
An in vitro study was conducted to determine if sodium bicarbonate would interfere with H2O2 decomposition (Sharma [Report], 1996). When 3% hydrogen peroxide gel mixed 1:1 with water was held in human saliva for up to 12 minutes at 37oC, determination of oxygen generation indicated that the hydrogen peroxide was rapidly decomposed. The rate of decomposition was not affected by the presence of 5% NaHCO3 on its own or in a fluoride toothpaste formulation.
3.3.11.2 Exposure
According to SCCP (2007) the total amount of toothpaste ingested per application is 0.24 g and the frequency of application per day is 2. Thus, the exposure per day will be 0.48 g. Assuming 0.1% hydrogen peroxide, the amount of hydrogen peroxide ingested per day will be 0.48 mg. With a body weight of 60 kg this will represent (0.48/60) 0.008 mg/kg bw/d.
According to SCCP (2007) the total amount of mouth-rinses ingested per application is 1.0 g and the frequency of application per day is 3. Thus, the exposure per day will be 3.0 g. Assuming 0.1% hydrogen peroxide, the amount of hydrogen peroxide ingested per day will be 3.0 mg. With a body weight of 60 kg this will represent (3.0/60) 0.05 mg/kg bw/d.
3.3.11.3 Clinical studies and post-marketing experience with toothpastes containing hydrogen peroxide
Two clinical studies have been conducted to evaluate the change in microbiological flora associated with repeated use, twice daily for six months, of hydrogen peroxide/sodium bicarbonate toothpastes (0.75% H2O2 with 5% NaHCO3 and 1.5% H2O2 with 10% NaHCO3). The results showed a low level of yeast recovery throughout the studies, including the final 3 months when all subjects were using the control product (sodium fluoride toothpaste). Evaluation of the gingival status of the subjects revealed no increase in bleeding points and there were no trends in alteration of shade of teeth during the study. Finally, no soft tissue changes attributable to use of any of the products were observed (Fischman et al., 1992, [Abstract], 1992 b).
Ten additional studies are reported in which toothpaste formulations containing hydrogen peroxide up to 1.5% were tested in humans (Table 3.7). In one study the subjects had undergone surgery (Dentino et al., 1995), in the other studies all were healthy subjects. In controlled studies, the incidence of reporting unwanted effects was similar between subjects using a hydrogen peroxide formulation and those in the control groups.
Table 3.7: Summary of clinical studies using hydrogen peroxide toothpastes
Other clinical trials up to 6 months in length have been conducted with toothpastes containing up to 3% hydrogen peroxide. The trials, along with reported adverse events are summarised in Table 3.8. In none of the trials have adverse events been reported which were related to use of toothpaste with hydrogen peroxide.
Toothpastes which contain 0.75% H2O2 are available in USA. In the 3 years between 1991 and 1994, 40.6 million units of these toothpastes were sold and over the same period the Cosmetic, Toiletry and Fragrance Association (CTFA, 1994) received 421 reports of adverse events; this equates to about 1 report for each 100,000 units. The most common reactions reported were oral irritation and burning mouth. Symptoms usually resolved on withdrawing the product. This rate of reporting and the nature of the reports are similar to that for other toothpastes marketed in the USA (COLIPA, 1998).
Since 1995, dual phase toothpastes which consist of a blue gel phase containing 1.5% hydrogen peroxide and a white paste phase with 10% sodium bicarbonate have been available in the USA. The two phases are delivered simultaneously and in equal amounts from a pump dispenser to give a final hydrogen peroxide concentration of 0.75%. The total number of units of this product (0.5, 3.5, 5.2 and 10.4 oz, corresponding to approximately 15, 100, 149 and 300 ml). sold in the period 1995-1997 was 181 millions. During that time, a total of 1223 unfavourable reports were received, of which 977 were considered to be possible adverse reactions (unpublished company data) (COLIPA, 1998). A breakdown of the complaints is given in Table 3.9.
3.3.11.4 Clinical studies and post-marketing experience with mouth-rinses containing hydrogen peroxide
Use of 3% hydrogen peroxide 3 to 5 times per day as a mouth-rinse resulted in mucosal irritations in 2 individuals with prior tissue injury. The pre-existing lesions worsened after exposure to hydrogen peroxide (Rees and Orth, 1986). Herrin et al. (1987) have shown that use of 3% hydrogen peroxide with sodium bicarbonate did not cause lesions in healthy individuals. Gingival lesions were seen in patients who used home care solutions employing 5 M sodium chloride in addition to 3% hydrogen peroxide and sodium bicarbonate.
A group of 88 dental students self-administered 6-12.5% hydrogen peroxide. They used it as a mouthwash and dipped their toothbrushes into the solution before brushing their teeth. Application of the hydrogen peroxide was 2-3 times per day for 1-2.5 months. Some gingival changes were noted: 6.4% of the subjects showed “redder” gums, 3.4% showed “paler” gums, and 6.6% developed hyperkeratinised filiform papillae of the tongue (Miller et al., 1938).
When adolescents with fixed appliances (n=30) used a 1.5% hydrogen peroxide solution as a mouth-rinses once every day for 18 months there was no evidence of oral irritation (Boyd, 1989). Similarly there were no reports of adverse events in a study in which 93 subjects rinsed three times a day for 7 days with a 1.5% hydrogen peroxide solution; this study included a control group of 85 subjects (Gomes et al., 1984).
In a clinical study, 58 patients used a mouth-rinse containing 1.5% hydrogen peroxide four times a day for 3 months. The patients were monitored at baseline and after 30, 60 and 90 days including an intraoral examination of soft tissues. There were no side effects associated with the soft tissues and no reports of irritation (Winer et al., 1991).
In a 21-day gingivitis study in humans using a hydrogen peroxide/sodium bicarbonate mouth-rinse, no local adverse reactions were seen which were attributable to the hydrogen peroxide/sodium bicarbonate system (Purdue University [Report], 1990). Summary of human safety data of hydrogen peroxide in mouth-rinses is shown in Table 3.10.
Table 3.10: Summary of human safety data of hydrogen peroxide in mouth-rinses
A 1.5% hydrogen peroxide mouth-rinse has been marketed in the USA since 1985. Between 1985 and 1995, 10 million 8 oz bottles (approximately 240 ml) and 300,000 32 oz (approximately 960 ml) bottles have been sold. Over the same period of time, 39 complaints were received (COLIPA, 1998).
An aqueous based dual phase product which consisted of a blue phase containing 1.5% hydrogen peroxide and a white phase with 10% sodium bicarbonate, has been marketed in the USA since 1995. The two phases are delivered simultaneously and in equal amounts from a dispenser to give a final hydrogen peroxide concentration of 0.75%. The total number of units (2, 10, 20 and 30 oz i.e. 60, 300, 600, 900 ml) of mouth-rinse sold in the period 1995 - 1997 was 24 millions. During that time, a total of 501 unfavourable reports were received of which 192 were considered to be possible adverse reactions (unpublished company data). A breakdown of the complaints is given in Table 3.11 (COLIPA, 1998).
3.3.11.5 Summary / Comment on human data – Tooth paste and mouth rinses
Several clinical studies with toothpaste and mouth-rinses containing up to 3% hydrogen peroxide have been carried out. All studies seem to have been conducted or sponsored by the manufactures. The duration of the toothpaste studies varied from 48 hours to 6 months. Only two studies (with a total of 165 persons) had a duration of 6 months. No product related adverse events were mentioned. No treatment-related effects were reported in studies with mouth-rinses containing 1.5% hydrogen peroxide. A 3% hydrogen peroxide solution used as a mouth-rinse 3 to 5 times daily caused mucosal irritation especially if the oral mucosa is already damaged. There is a need for independent long-term studies both with toothpaste and mouth-rinses.
Source & ©: SCCP,
The SCCP opinion states:
3.3.11.6 Exposure
Exposure studies (study no. 2000045 and 2000143) were carried out by Procter & Gamble. Adult subjects (N=12) used either a 5.3% hydrogen peroxide gel strip that delivers 10.6 mg hydrogen peroxide/strip (200 mg of a 5.3% hydrogen peroxide gel; 5, 10, 30 or 60 minute treatments), a 10% carbamide peroxide (CP) tray that delivers ≈ 22-48 mg hydrogen peroxide (600-900 mg of a 3.6% hydrogen peroxide gel; 10, 30, 60 or 120 minute treatments) or a 20% CP tray that delivers ≈ 40-60 mg hydrogen peroxide (600-900 mg of a 6.7% hydrogen peroxide gel; 10, 30, 60 or 120 minute treatments). Treatment was on maxillary teeth only. It is concluded that hydrogen peroxide delivered at 6% in tooth whitening products (films, gels or varnished) intended for direct application to the teeth, degrades rapidly during wear time. This is indicative of the rapid degradation of hydrogen peroxide that would occur where direct contact with the gingival tissues immediately surrounding the teeth may result during wear time of such tooth whitening products. Salivary hydrogen peroxide levels are low during wear time (<0.02%), thereby demonstrating the minimal oral and systemic exposure that occurs with such tooth whitening formulations. The available peroxide resulting from the cosmetic use 4 strips with 6% hydrogen peroxide will be about 50 mg hydrogen peroxide per day (200 mg of 6% hydrogen peroxide = [200x0.06] x 4 = 48 mg).
If the mean (Table 3.12) is used to calculate exposure this will correspond to (4.8/60) 0.08 mg/kg bw/d while if a maximum exposure of 11.4 mg is used, this will correspond to (11.4/60) 0.19 mg/kg bw/d (The calculations are based on a salivary flow of 0.3 ml/min, while the flow when stimulated is 1.5 – 2.0 ml/min. Since application of the strips most likely will stimulate salivary flow, the numbers given are probably to low).
For comparison, Haywood and Haymann (1989) estimated in an early study that the approximate dose of carbamide peroxide for each application was 90 mg. The advances in technique for preparing custom fitted trays and the improvement in whiteners now allow the use of much less material for each application. A recent estimation indicates that an average amount of commercial whitener used clinically for 10 maxillary teeth (full arch) was 502 mg per application (Li, 1996). The whitener contained 10% carbamide peroxide. It was estimated that about 10% of the applied whitening gel might be consumed during the application (Dahl and Becker, 1995). Therefore, an individual of 60 kg bodyweight, the exposure to tooth whitener was calculated at [50.2/60] 0.84 mg/kg/day, and the exposure to carbamide peroxide through tooth whitener containing 10% carbamide will be 0.084 mg/kg/day, corresponding to 0.028 mg/kg/day of hydrogen peroxide. Dahl and Becker (1995) point out that overfilling of the tray and excessive biting on the tray are factors that may cause additional release of the bleaching agent. Matis et al. (2002) have concluded that 25% of carbamide peroxide in the tray is swallowed. This will correspond to about 0.07 mg/kg/day.
In the case of the gel strips it has been reported that the user occasionally may swallow the strip. This will result in an exposure of about 12 mg hydrogen peroxide.
The above calculation of daily exposure is claimed to be conservative as it assumed a constant concentration of 10% carbamide peroxide in whitener during the whole application. Several studies have shown that peroxide content decreases with time, particularly significant during the early part of application (ADEPT [Report], 1991, Christensen [Abstract], 1997, Nathoo et al. [Abstract], 1996 Ploeger et al. [Abstract], 1991). In a recent study it was reported that the carbamide peroxide degradation in bleaching trays occurred in an exponential manner and that 10% remained after 10 hours (Gaiao et al. [Abstract], 1998). On the other hand, it may be expected that the exposure is highest in connection with the process of inserting the night guard.
Comparisons of the use of the new strips with the custom fitted trays suggest that the total exposure to hydrogen peroxide is of the same order of magnitude.
The degradation of 10% carbamide peroxide (≈3.6% hydrogen peroxide), worn in a custom-fitted tray, was determined over 10 hours (N=15). The degradation rate in the tray and in the gel on the teeth was rapid for the first hour, and then slowed, with more than 50% loss of active ingredient seen at 4 hours, and more than 85% loss following 10 hours of exposure. The degradation of “grab” sample from the reservoir of tooth no. 8 was slower. On average 56% remained after 4 hours and 23% after 10 hours (Matis et al., 1999).
In an article by Mahony et al. (2003), both maxillary and mandibular teeth were treated with a 5.3% hydrogen peroxide paint-on gel. Peroxide concentrations in the tooth scraping sample after 10, 30 minutes, 1, 2 and 4 hours of daytime wear were 4.56, 3.28, 1.57, 0.51 and 0.14%, respectively. The median peroxide concentration in the saliva at 5, 10 and 20 minutes of daytime wear were 0.001, 0.0001 and 0.0001% respectively. The median peroxide concentrations in the saliva at 30 and 60 minutes were below the limit of detection (0.00007%). Overall, salivary hydrogen peroxide concentration was less than 0.033% measured at any time.
Bleaching strips containing 10% hydrogen peroxide gel were used in a clinical trail involving 16 persons. The median hydrogen peroxide concentration after 5 minutes was 7.3%, 6.4% and 0.7% for strips, teeth and gingival, respectively, declining to 4.6%, 2.9% and 0.1% at 30 minutes. Salivary samples never exceeded a median concentration of 0.014% at any point. Median hydrogen peroxide concentration on strips and teeth remain about 2% over 60 minutes. (In the received summary report, it is written that 14% hydrogen peroxide strips was used) (Walden et al., 2004, report).
Maxillary teeth were treated with 14% hydrogen peroxide strips (100 mg gel load) in a clinical trial involving 15 persons. The concentration was 13.4% on average after sampling 3 strips. The median concentration for the teeth after 10 minutes was 6.9% after 30 minutes 4.2% and 60 minutes wear time 2.9%. Using colorimetric analysis with glycerine normalized analysis, the results after 10 minutes was 11.1%, 30 minutes 8.7% and 60 minutes 8.5%. Thus, there is a considerable difference which increases with time. The highest concentration in saliva was 0.073%, which occurred at 10 minutes time point. Strip hydrogen peroxide level decreased with wear time. After 30 minutes wear time, the median peroxide level on the strip ranged from 3.4 to11% depending on the analytical method. Tooth hydrogen peroxide level also decreased with wear time. Depending on the analytical method the median peroxide concentration was 10.0 to12.7% after 5 minutes of wear time and the levels ranged from 4.2 to 8.7% after 30 min. Median salivary peroxide level did not exceed 0.073% for any time point in the study (Report 2003 009).
Slezak et al. (2002) determined the concentration of hydrogen peroxide in saliva after application of a 6.5% hydrogen peroxide paint-on gel. The concentrations were 0.03%, 0.0042% and 0.0001% at 1, 5 and 15 minutes, respectively.
A study involving 17 persons was carried out with 6.5% hydrogen peroxide strips (0.2 g gel load, 13 mg hydrogen peroxide/strip) or 14% hydrogen peroxide strips (0.1 g gel load, 14 mg hydrogen peroxide/strip). The median peroxide concentrations are shown on Table 3.13. It is pointed out that for pair wise comparisons between treatment, there were no significant differences between the strips hydrogen peroxide level at 60 min and for gingival and saliva data for any time point and for area under the curve (Report 2003 046).
The use of 5.3% or 6.5% hydrogen peroxide paint-on gel is presented in a clinical study involving 17 persons. When 6.5% paint-on gel is used, median concentrations after 2 and 5 minutes when retractor is used was 8.6% and 9.5%, respectively. In another study with no retractors, the concentration 0.5 minute after application was 10.6%. This increase after application is probably due to the rapid loss of alcohol in the gel (Report 2003 043).
In a study where 6.5% hydrogen peroxide paint-on gel and 6% hydrogen peroxide strip were compared, it was concluded that on the average the hydrogen peroxide concentration on teeth and in saliva was statistically higher for strips compared to paint-on gel both at 5 and 30 minutes time point, while the concentration of paint-on appear to peak at 30 seconds application, the hydrogen peroxide concentration rapidly declined to less than 0.6% at 2% as the paint-on products exposed to saliva, salivary hydrogen peroxide peaked at 0.5 minutes (0.034%) and declined rapidly (Report 2002 126).
Other studies
The amount of peroxides released into saliva was related to the bleaching system and only partially influenced by the individual salivary flow rate. Bleaching with Vivastyle (10% carbamide peroxide, tray charged with 225 mg) led to lower release of peroxides into saliva compared to Whitestrips (5% H2O2) (Vivastyle: 0.8± 0.17 mg; Whitestrips: 1.5±0.84 mg). The peak exposures of hydrogen peroxide in the saliva were 0.06% with Vivastyle and 0.1% with Whitestrips. . This will correspond to about 5 µg/cm2. Salivary flow rate was not correlated to release of peroxides from the bleaching products (Hanning et al., 2003).
Hannig et al. (2006) compared the hydrogen peroxide recovery in saliva during use of different home bleaching products in smokers and non-smokers. Peroxide recovery was evaluated with respect to the safe level reported In the literature. Four different bleaching regimes were used by 10 smokers and 10 non-smokers: Whitestrips, Vivastyle (tray-based) and two paint on products (Crest Night Effects, Colgate Simply White). Whole saliva was collected and total amount of peroxide (mg) released during the 60 min bleaching period was determined: Colgate Simply White: 2.67 + 0.88 (non-smokers); 2.66 + 1.17 (smokers); Crest Night Effects: 0.23 + 0.13 (non-smokers); 0.25 + 0.16 (smokers); Vivastyle: 2.47 + 0.82 (non-smokers); 2.44 + 1.31(smokers); Whitestrips: 1.39 + 0.62 (non-smokers); 2.02 + 1.86 (smokers). In terms of amount of peroxide per kg body weight the bleaching systems led to a single exposure of 0.046 mg/kg bw. The authors concluded that smoking did not affect the degrading of hydrogen peroxide from bleaching products. Significantly lower amounts of peroxide were detected in saliva during application of the paint-on product Crest Nights Effects compared with the other bleaching systems.
3.3.11.7 Summary / Comment on exposure
It is difficult to assess the exposure, which may vary with the product and the level of active material (hydrogen peroxide) used.
In a study were salivary hydrogen peroxide was determined using a 6% hydrogen peroxide strip, assuming a salivary flow of 0.3 ml/min, the calculated exposure from 4 strips a day was 0.08 mg/kg bw/d. If mean + 2SD is used the exposure will be 0.17 mg/kg bw/d. It should be noted that the numbers may be minimum numbers since application of the strips most likely will stimulate salivary flow, which may be as high as 2.0 ml/min. Thus, the exposure may be underestimated.
The total amount of peroxide (mg) released during a 60 min bleaching period was determined from whole saliva collections with 4 different bleaching regimes (two tray-based [Whitestrips, Vivastyle] (tray-based) and two paint on products [Crest Night Effects, Colgate Simply White]). Amount of hydrogen peroxide released; Whitestrips: 1.39 + 0.62 mg, Vivastyle: 2.47 + 0.82 mg, Crest Night Effects: 0.23 + 0.13 mg, and Colgate Simply White: 2.67 + 0.88 mg. In terms of amount of peroxide per kg body weight the bleaching systems led to a single exposure of maximum 0.046 mg/kg bw of hydrogen peroxide (Colgate Simply White). Smoking did not affect the degrading of hydrogen peroxide from bleaching products.
The concentration of hydrogen peroxide in contact with the teeth will be close to the concentration in the bleaching product. The gingival concentration of hydrogen peroxide has been reported to be about 0.7% and 0.6% 5 minutes after application of a strip containing 10% and 6.5% hydrogen peroxide. The level was reduced to 0.1% and 0.2%, respectively after 30 min.
The maximum concentration of hydrogen peroxide in the saliva after teeth bleaching has been reported to be 0.1% corresponding to about 5 µg/cm2. The saliva concentration seems to be similar with a 200 mg strip containing 6.5% hydrogen peroxide and a 100 mg strip containing 14% hydrogen peroxide.
For gel strips it has been reported users occasionally may swallow the strip, resulting in an exposure of about 12 mg hydrogen peroxide (0.2 mg/kg bw). When trays are used, overfilling of the tray and excessive biting on the tray are factors that may cause additional release of the bleaching agent.
From the exposure studies the systemic absorption of hydrogen peroxide is estimated to be in the range from 0.03 mg/kg bw/d to 0.2 mg/kg bw/d. Consequently, an exposure from tooth whitening products with 6% hydrogen peroxide of 0.2 mg/kg bw/d may be used in safety calculation.
Source & ©: SCCP,
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