Abstract
Letter to the Editor
In the context of the Expert Panel Safety Assessments, the Cosmetic Ingredient Review (CIR) Expert Panel prepared a final report on some denatured alcohols and denaturing agents, 1 including denatonium benzoate (CAS Number: 3734-33-6), which is widely known as the main bitter denaturant intentionally added to non-potable alcohol to cause an unpleasant taste and thus discourage ingestion. Although the document was reviewed for the cosmetics industry and published in 2008, it is of importance in present days, and for a more diverse audience, due to the increased use of denatured alcohol for disinfection. As the COVID-19 pandemic has increased the global use of diverse products for daily disinfection (for hands, supermarket products, household objects and surfaces, health facilities, public spaces, footwear, etc.), the use of denatured alcohol has increased extensively; in turn, human exposure to denatonium benzoate has exceeded previous levels. In this panorama, a new reconsideration of the toxicity profile of denatonium benzoate is necessary.
Since denatonium benzoate (Bitrex®) is at the moderate-to-slight acute oral toxicity boundary, with a median lethal dose (LD50) of 500-900 mg/kg for experimental animals,1-3 its addition to household products has been suggested at concentrations that under normal exposure from typical use do not induce acute oral toxicity in humans.1,2 But, given the present potential for daily exposure, some questions arise: (a) Since inhalation toxicity cannot be reliably predicted from oral toxicity values, 4 what about the acute toxicity by inhalation of denatonium benzoate, as absorption by inhalation can occur when spraying denatured alcohol for disinfection? (b) As solid particles of denatonium benzoate clearly remain on the disinfected surfaces after evaporation of alcohol (which can be easily detected with a simple tasting experiment), including the hands (which can lead to dermal penetration and even recurrent accidental ingestion), what about the chronic toxicity? Well, there are no concrete answers. Surprisingly, the toxicity profile of denatonium benzoate is not complete: according to the conclusion of the European Food Safety Authority (EFSA) on the peer review of the risk assessment of denatonium benzoate, 3 published in 2012, there are no data or no valid data on the toxicokinetics, short- and long-term toxicity, reproductive and developmental toxicity, carcinogenicity, and neurotoxicity. Furthermore, it is known that denatonium benzoate is not readily biodegradable.2,3 As such, it is a water pollutant for which there is not enough information on its impact on the environment (see the work of Lege et al 5 entitled “Denatonium–A so far unrecognized but ubiquitous water contaminant?”). All of these gaps can be corroborated by a close inspection of the final report reviewed by the CIR Expert Panel, 1 in which the available data for the related compound lidocaine were sometimes used to complete the toxicity profile of denatonium benzoate. Despite all the previous uncertainties, denatonium benzoate has been widely used as a deterrent in diverse products, sometimes mandatorily, and now it is part of the products whose global market is analyzed in terms of growth projections due to the COVID-19 pandemic. 6
In addition, inappropriate immunological responses to denatonium benzoate could be an important problem. In particular, the possible sensitization to denatonium benzoate due to repeated exposure and its impact on COVID-19 patients are relevant concerns. Unfortunately, there are only a few reports available in the scientific or medical literature documenting adverse reactions to denatonium benzoate7-11; indeed, since adverse reactions to this denaturing agent could be difficult to recognize, 9 it is expected that most of the cases in the population have not been reported. However, when analyzing these few published case reports of adverse reactions to denatonium benzoate,7-11 the following conclusions come to light: (a) Denatonium benzoate can provoke asthma exacerbation or other reactions when inhaled,7-11 especially when a history of asthma or allergies exists8-11 and perhaps, in part, when there is underlying diabetes and/or hypothyroidism. 9 (b) Denatonium benzoate can definitely induce sensitization, at least in a certain group of individuals10,11 (as previously suggested by Youakim8,9). Because asthma and diabetes are conditions that increase the risk of severe illness from COVID-19,12,13 and since denatonium benzoate could complicate respiratory conditions,8,9,11 the use of denatured alcohol could constitute a serious risk for a certain vulnerable group. As the susceptible individuals are not well identified and since the knowledge about all potential medical conditions that could be associated with risk for severe COVID-19 outcomes is still limited,12,13 denatonium benzoate-related complications may go unnoticed for both the patients themselves and the health care professionals.
Recurrent disinfection habits are now part of our daily life (and likely of our future life). The repeated use of hand sanitizers, in which denatured alcohol may be the main active ingredient, is a clear example of current disinfection habits. In view of this, the use of denatonium benzoate as a denaturant should be reconsidered. After all, its addition to non-potable alcohol seems to serve traditional protocols rather than merely health purposes, and, very importantly, its effectiveness as a deterrent to ingestion has been questioned. 2 For example, information recently provided by Mehrpour and Sadeghi 14 for alcohol-related poisoning cases in Iran indirectly demonstrated that denatonium benzoate is not a deterrent to the ingestion of denatured alcohol when people are determined to consume it (especially amid the COVID-19 pandemic in an unfounded attempt to fight the coronavirus). Also, in a related case of products with denatonium benzoate, Perron et al 15 recently commented regarding computer duster sprays that “no evidence exists that demonstrates DB [denatonium benzoate] being effective in deterring intentional inhalation.” This information suggests that denatonium benzoate is not very effective as a deterrent to ingestion and inhalation.
In conclusion, denatonium benzoate is not really required as a non-potable alcohol denaturant and, due to the potential health risks associated with the exposure to this compound, its use should be reconsidered. The use of denatonium benzoate-free disinfectants should be promoted as an alternative; a list of affordable household disinfectants that deserve discussion was suggested by Gercina et al. 16 Additionally, we encourage toxicology researchers and, especially, the CIR Expert Panel, to update the toxicity profile of denatonium benzoate. Cases of allergy and sensitization should also be reviewed in detail. Last but not least, the environmental impact of denatonium benzoate should be properly addressed, since the EFSA suggested in 2012 regarding denatonium benzoate that “if other uses resulting in higher exposure were intended in the future, a considerable amount of data would be needed to finalise the environmental exposure assessment.” 3 We have now encountered that “future” situation.
