Office of Pesticide Programs (OPP)
Regulatory Public Docket (7502P)
Environmental Protection Agency
1200 Pennsylvania Ave., NW.
Washington, DC 20460-0001
October 20, 2008
Regarding: Docket EPA-HQ-OPP-2006-0573; FRL-8376-9
Proposed Quaternary Ammonium Compound Food Tolerance Exemption
To Whom It May Concern:
The Environmental Working Group (EWG) is a non-profit public health and environmental research and advocacy organization based in Washington, DC, and Oakland, CA. We focus much of our research on potential health risks from exposures to hazardous chemicals that contaminate food, water, and the environment, or that are used as ingredients in consumer products. We write to express our concern over a proposed EPA action, requested by a manufacturer, which could potentially double human exposure to the antimicrobial agent ADBAC, despite the existence of significant health and safety data gaps surrounding the substance.
With this letter, we register our objection to EPA’s proposal to remove the food tolerance requirement specific to food preparation settings for n-alkyl (C12-18) dimethyl benzyl ammonium chloride (commonly referred to as ADBAC, CAS No. 68424-85-1, within the benzalkonium chloride class of chemicals), a widely recognized asthmagen and potential reproductive toxicant used in a broad range of commercial and household cleaners and other consumer products. We advocate that EPA maintain a food tolerance requirement associated with ADBAC that protects the most vulnerable segments of the human population, and considers the impact of multiple sources of exposure to this potent pesticide.
In the food preparation setting, products containing ADBAC may be used to sterilize any and all food-contact surfaces in public eating places such as restaurants and cafeterias, as well as dairy processing equipment, food processing equipment, and utensils. Given the likelihood that food itself could become contaminated with ADBAC, EPA is required to set a legal tolerance level for residues of this pesticide in food, or the maximum amount of ADBAC residue that can legally contaminate food products. Currently, EPA exempts from this food tolerance requirement all ADBAC sterilizing products containing 200 ppm or less of the active ingredient; the current action, specifically requested by Edwards-Councilor Co., Inc., makers of ADBAC sterilizing products for food preparation settings, would extend this exemption to products containing 400 ppm or less of the pesticide.
In supporting this food tolerance exemption, EPA conducted a cursory risk assessment of the effects of increased exposure (EPA 2008), based on their 2006 risk assessment of ADBAC (EPA 2006). Review of available toxicological and epidemiological research on ADBAC and other quaternary ammonium compounds (QACs) reveals substantial data gaps and significant cause for concern regarding impacts to human health and the environment in both risk assessment documents. In proposing a food tolerance exemption for ADBAC in food preparation settings when sanitizing products contain no more than 400 ppm of the antimicrobial agent, EPA has neglected to consider the following issues of key relevance identified in the emerging body of science on QACs:
- Preliminary evidence indicates ADBAC and other QACs may be reproductive and genetic toxicants.
- Epidemiological and animal studies link these compounds to increased occupational asthma and immune system sensitization.
- Quaternary ammonium compounds are persistent in the environment and toxic at environmentally relevant concentrations.
- Overuse of QACs may lead to development of antimicrobial resistance.
- Conditions common to food preparation impair the sterilization efficacy of QACs.
EPA would be ill-advised to exempt this antimicrobial agent from food residue tolerance requirements under any circumstances, given its widespread use in commercial and consumer products, and growing concerns about its adverse impacts to human health and the environment. Instead, EPA must demand additional safety studies, and reevaluate current uses of ADBAC and other QACs in light of emerging information.
Details regarding current health and safety concerns surrounding ADBAC and other QACs are provided below.
Preliminary evidence indicates ADBAC and other QACs may be reproductive and genetic toxicants. A research brief published in leading scientific journal Nature in June 2008 details the detective work of Dr. Patricia Hunt of Washington State University at Pullman, as she investigated the cause of a severe decline in the fertility of her laboratory mouse population following a move from Case Western Reserve University in Cleveland, Ohio in 2005 (Hunt 2008). The culprit: the disinfectant Virex, containing both ADBAC and the QAC didecyl dimethyl ammonium chloride (DDAC), used to clean the mouse cages in the new animal facility.
EPA’s 2006 review of ADBAC cites a single reproductive toxicity study of rats exposed via food that provides a NOAEL of 65.4 mg/kg/day for male offspring, and 79.9 mg/kg/day for female offspring (Neeper-Bradley 1990). Dr. Hunt’s experience with increased incidence of infertility and birth defects in laboratory animals kept in cages cleaned with QACs, later corroborated by other researchers and lab managers (Hunt 2008), suggests additional work is needed, particularly surrounding variations in toxic effects for different species and different routes of exposure. EPA’s dismissal of ADBAC’s potential to affect reproduction must be revised in light of this new evidence.
Recent tests using human blood cells conducted by scientists at the Institute of Cancer Research within the Medical University of Vienna, Austria, indicate that benzalkonium chloride and other QACs can produce genotoxic effects at low levels (Ferk 2007). According to the researchers: “… the direct contact of humans to QAC-containing detergents and pharmaceuticals that contain substantially higher concentrations than those which were required to cause effects in eukaryotic cells in the present study should be studied further in regard to potential DNA-damaging effects in man.” (Ferk 2007)
It would be reckless to allow increased exposures of the American population to ADBAC, through encouraging use of more concentrated ADBAC sterilizing products via elimination of health protections, without more extensive studies on its reproductive and genetic toxicity. ADBAC and other QACs are in wide use in commercial cleaning products used in hospitals, offices, and food preparation facilities, as well as in household cleaners. Thus, it is essential that EPA move quickly to limit exposures to these ubiquitous chemicals, while actively building a greater dataset regarding their effects on fertility, birth defects, and DNA damage.
Epidemiological and animal studies link these compounds to increased occupational asthma and immune system sensitization. Quaternary ammonium compounds used as cleaning agents were found to cause or exacerbate asthma, according to a 2004 review by scientists associated with the Collaborative on Health and the Environment (HCWH 2006). A list of asthmagens prepared by the Association of Occupational and Environmental Clinics, which draws largely on case reports and follow-up clinical tests of workers, specifically linked benzalkonium chloride, the class of chemicals including ADBAC, to occupational asthma, along with dodecyl-dimethyl-benzylammonium chloride and lauryl dimethyl benzyl ammonium chloride (HCWH 2006). Estimates of the proportion of newly developed adult asthma cases related to the working environment range from 5 percent to 29 percent (Pechter 2005), with the American Thoracic Society providing an estimate of the occupational contribution to adult onset asthma of 15 percent (American Thoracic Society 2003). EPA did not consider the growing body of evidence concerning occupational asthma in its risk assessments of ADBAC (EPA 2006, 2008).
Widespread use of QACs as disinfectants in the hospital setting has resulted in creation of a large health care worker population from which to draw case studies and epidemiological information linking these chemicals to occupational asthma. Data provided by asthma surveillance systems in California, Massachusetts, Michigan, and New Jersey for years 1993 through 1997 indicate that health care workers accounted for 16 percent of the 1,879 confirmed cases of work-related asthma, but only 8 percent of the states’ workforce (Pechter 2005). The disproportionate burden of work-related asthma in the health sector suggests that exposures to chemicals in health care settings may be involved. Nurses were most frequently affected by work-related asthma, and exposures to cleaning products were most frequently reported in conjunction with asthma onset (Pechter 2005).
A survey of 3,650 health care workers in Texas revealed that the likelihood that these workers developed asthma during their careers doubled if they performed general cleaning of surfaces as part of their jobs (Delclos 2007). Quaternary ammonium compounds, bleach, citric-acid based cleaners, glutaraldehyde and paraffinic hydrocarbons were among the active ingredients identified by this study as likely asthmagens. In 2000, researchers at the University hospital in Strasbourg, France, reported three case studies of nurses who manifested asthma symptoms directly correlated with their exposure to benzalkonium chloride disinfecting solutions in controlled tests (Purohit 2000). A further health concern emerging from the medical setting, benzalkonium chloride and other QACs, when used in medical bandages, antiseptics, and disinfectants, are well-known to cause contact dermatitis (Wong 2001). Again, such real-world considerations were neglected in EPA’s risk assessments of ADBAC (EPA 2006, 2008).
Study of a very different occupational group provides further evidence of the role of QACs as immune system sensitizers. A 1996 epidemiological study of 194 Dutch pig farmers noted atopic sensitization, defined as the increase in production of the immunoglobulin IgE in response to common allergens, was found to occur more frequently in farmers who used QAC disinfectants, and that this sensitization was related to respiratory symptoms consistent with asthma (Preller 1996). This evidence indicates that occupational exposure to QACs may induce IgE sensitization to common allergens, an important risk factor for the development of symptoms consistent with asthma.
Animal studies confirm the ability of QACs to act as immune system sensitizers. Research by the Danish National Institute of Occupational Health in 2004 found evidence that subcutaneous injections of specific QACs in mice could trigger increases in levels of antibodies including IgE, IgG1 and IgG2, while injections of some QACs in combination could produce synergistic sensitizing effects (Larsen 2004a). The results of this study suggest that many QACs have significant sensitizing activity, and combinations of compounds may stimulate disproportionate immune reactions.
The Danish National Institute of Occupational Health also looked specifically at the sensitizing effect of benzalkonium chloride in mice (Larsen 2004b). In this study, a 0.1 microgram dose injected subcutaneously into female mice showed a statistically significant sensitizing effect (e.g. an increased level of IgE). Interestingly, higher doses of benzalkonium chloride occasionally seemed to suppress IgE and IgG1 antibodies. None of these studies were evaluated by EPA as part of their ADBAC risk assessments (EPA 2006, 2008).
This emerging body of evidence signals significant concern regarding ADBAC and other QACs as immune sensitizers, and specifically as occupational asthmagens when inhaled through exposure to cleaning and sterilizing products. In its risk assessment of ADBAC, EPA uncovers no toxicological data using inhalation as a route of exposure, but admirably uses an oral exposure study with an additional uncertainty factor to assess risk via inhalation (EPA 2006). While this may be an appropriate use of existing data for initial risk assessment, it is unacceptable to exempt more concentrated ADBAC products from a food tolerance requirement without further study of this critical health concern.
Quaternary ammonium compounds are persistent in the environment and toxic at environmentally relevant concentrations. Benzalkonium chloride and other QACs are commonly detected in treated wastewater and sewage sludge, and are most concentrated in sediments near wastewater discharge sites (Ferrer 2001, 2002; Sun 2001; Martinez-Carballo 2007a, 2007b). The high affinity of these compounds for soil suggests that they preferentially concentrate in sediment, rather than in water (Ferrer 2002). Increased use of these compounds thus may trigger increased levels of contamination in river and coastal sediments, and in agricultural lands through application of biosolids. EPA’s analysis of the environmental fate of ADBAC (EPA 2006) relies substantially on an unreviewed industry document claiming that the pesticide is biodegradable, rather than on real-world measurement of ADBAC in the environment.
Recent studies of genotoxicity at environmentally relevant concentrations indicate benzalkonium chloride and other QACs can trigger DNA damage in plant and mammal cells at low levels (Ferk 2007). According to the researchers: “Our findings show that both chemicals induce moderate but significant genotoxic effects in eukaryotic cells at concentrations which are found in wastewaters and indicate that their release into the environment may cause genetic damage in exposed organisms.” (Ferk 2007)
These new findings concerning genetic toxicity, published after EPA’s 2006 risk assessment, signal caution is needed in evaluating the appropriateness of any exemptions to food tolerance requirements for a persistent and ecotoxic pesticide like ADBAC. A revised risk assessment associated with a regulatory change that would increase the concentration of ADBAC products used in food preparation settings and, therefore, increase the levels of ADBAC flowing through wastewater treatment systems and into the environment, should incorporate the latest ecotoxicological data.
Overuse of QACs may lead to development of antimicrobial resistance. Laboratory evidence and common sense indicate that microbes can develop resistance to the antibiotic effects of QACs, rendering the pesticide ineffective. In addition, exposing specific bacterial strains to QACs appears to result in selection favoring bacteria that are resistant to multiple antibiotics (Karatzas 2008). Identification of QAC-resistant genes in plasmids easily transmitted between bacterial species suggests the spread of resistance could occur with relative ease (Bjorland 2003; Nakaminami 2007).
Such concerns are no longer theoretical: A recent investigation at a food-processing facility revealed the presence of bacterial colonies specifically resistant to benzalkonium chlorides (Mullapudi 2008). The researchers described the test site, a turkey-processing facility, as a potential reservoir for bacteria harboring resistance to QACs.
EPA did not evaluate risks associated with development of antimicrobial resistance in its assessments of ADBAC (EPA 2006, 2008). In light of this new evidence, it would be reckless for EPA to eliminate this food tolerance requirement for more concentrated ADBAC solutions, a move that would encourage increased use of ADBAC and other QAC products in food-processing settings.
Conditions common to food preparation impair the sterilization efficacy of QACs. In a 2003 letter to FDA concerning benzalkonium chloride and other QACs, GOJO Industries, Inc., a well-known manufacturer of commerical and consumer cleaning products, states:
“The efficacy of quaternary ammonium compounds may be severely compromised during formulation and use. Benzalkonium chloride and benzethonium chloride may be neutralized by anionic or nonionic surfactants, hard water, proteins and other moieties.” (GOJO 2003)
Many of the conditions highlighted by GOJO are commonly found in food preparation settings. Thus, use of products containing ADBAC may not provide the antimicrobial action promised, and may instead lead to a false sense of security regarding cleanliness within food preparation facilities.
Growing health and efficacy concerns regarding ADBAC and other QACs justify a conservative approach regarding any policy changes that might increase exposures of everyday Americans to this pesticide. Environmental concerns indicate EPA must also evaluate the effects of these compounds within the larger environment, and take action to reduce their release into U.S. land and waterways. We thank EPA for the opportunity to provide these comments, and urge the Agency to address these issues thoroughly and promptly.
Rebecca Sutton, Ph.D. Senior Scientist
Jane Houlihan, PE, MSCE Vice President for Research
Environmental Working Group
1904 Franklin St., Suite 703
Oakland, CA 94612
ATS (American Thoracic Society). 2003. Occupational contribution to the burden of airway disease. American journal of respiratory and critical care medicine 167: 787-797.
Bjorland J, Steinum T, Sunde M, Waage S, Heir E. 2003. Novel plasmid-borne gene qacJ mediates resistance to quaternary ammonium compounds in equine Staphylococcus aureus, Staphylococcus simulans, and Staphylococcus intermedius. Antimicrobial agents and chemotherapy 47(10): 3046-3052.
Delclos GL, Gimeno D, Arif AA, Burau KD, Carson A, Lusk C, et al. 2007. Occupational risk factors and asthma among health care professionals. American journal of respiratory and critical care medicine 175(7): 667-675.
EPA (Environmental Protection Agency). 2006. Alkyl Dimethyl Benzyl Ammonium Chloride (ADBAC) Risk Assessment. EPA-HQ-OPP-2006-0339-0032. Office of Pesticide Programs, Antimicrobials Division, U.S. Environmental Protection Agency. August 1, 2006.
EPA (Environmental Protection Agency). 2008. Risk Assessment and Science Support Branch’s (RASSB’s) Review of Petition Submission to Amend 27 CFR § 178.1010 (b)41 and (c)36, and 40 CFR § 180.940 for Steramine 1G Tablets. EPA-HQ-OPP-2006-0573-0003. Office of Pesticide Programs, Antimicrobials Division, U.S. Environmental Protection Agency. February 20, 2008.
Ferk F, Misik M, Hoelzl C, Uhl M, Fuerhacker M, Grillitsch B, et al. 2007. Benzalkonium chloride (BAC) and dimethyldioctadecyl-ammonium bromide (DDAB), two common quaternary ammonium compounds, cause genotoxic effects in mammalian and plant cells at environmentally relevant concentrations. Mutagenesis 22(6): 363-370.
Ferrer I, Furlong ET. 2001. Identification of alkyl dimethylbenzylammonium surfactants in water samples by solid-phase extraction followed by ion trap LC/MS and LC/MS/MS. Environmental science & technology 35(12): 2583-2588.
Ferrer I, Furlong ET. 2002. Accelerated solvent extraction followed by on-line solid-phase extraction coupled to ion trap LC/MS/MS for analysis of benzalkonium chlorides in sediment samples. Analytical chemistry 74(6): 1275-1280.
GOJO. 2003. Proposed Rule; Reopening of the Administrative Record for Topical Antimicrobial Drug Products for Over-the-Counter Human Use; Health-Care Antiseptic Drug Products. 68 Fed. Reg. 32003. (May 29, 2003). [Docket No. 75N-183H]. Provided to FDA August 27, 2003.
HCWH (Health Care Without Harm). 2006. Risks to Asthma Posed by Indoor Health Care Environments: A Guide to Identifying and Reducing Problematic Exposures: Health Care Without Harm.
Hunt P. 2008. Lab disinfectant harms mouse fertility. Patricia Hunt interviewed by Brendan Maher. Nature 453(7198): 964.
Karatzas KA, Randall LP, Webber M, Piddock LJ, Humphrey TJ, Woodward MJ, et al. 2008. Phenotypic and proteomic characterization of multiply antibiotic-resistant variants of Salmonella enterica serovar Typhimurium selected following exposure to disinfectants. Applied and environmental microbiology 74(5): 1508-1516.
Larsen ST, Hansen R, Hammer M, Tegner U, Poulsen OM, Nielsen GD. 2004a. Adjuvant effect of quaternary ammonium compounds in a murine model. Toxicology letters 151(2): 389-398.
Larsen ST, Hansen R, Poulsen OM, Nielsen GD. 2004b. Adjuvant effect of benzalkonium chloride on the allergen-specific IgE, IgG1 and IgG2a antibody formation in BALB/cJ mice. Basic & clinical pharmacology & toxicology 95(2): 94-96.
Martinez-Carballo E, Sitka A, Gonzalez-Barreiro C, Kreuzinger N, Furhacker M, Scharf S, et al. 2007a. Determination of selected quaternary ammonium compounds by liquid chromatography with mass spectrometry. Part I. Application to surface, waste and indirect discharge water samples in Austria. Environ Pollut 145(2): 489-496.
Martinez-Carballo E, Gonzalez-Barreiro C, Sitka A, Kreuzinger N, Scharf S, Gans O. 2007b. Determination of selected quaternary ammonium compounds by liquid chromatography with mass spectrometry. Part II. Application to sediment and sludge samples in Austria. Environ Pollut 146(2): 543-547.
Mullapudi S, Siletzky RM, Kathariou S. 2008. Heavy-metal and benzalkonium chloride resistance of Listeria monocytogenes isolates from the environment of turkey-processing plants. Applied and environmental microbiology 74(5): 1464-1468.
Nakaminami H, Noguchi N, Nishijima S, Kurokawa I, So H, Sasatsu M. 2007. Transduction of the plasmid encoding antiseptic resistance gene qacB in Staphylococcus aureus. Biological & pharmaceutical bulletin 30(8): 1412-1415.
Neeper-Bradley T. 1990. Two Generation Reproduction Study in Sprague-Dawley (CD) Rats with Alkyl Dimethyl Benzyl Ammonium Chloride (ADBAC) Administered in the Diet: Project Report 52-52-254: Project Nos. 87-37-97105; 87-37-97109. Unpublished study prepared by Bushy Run Research Center.
Pechter E, Davis LK, Tumpowsky C, Flattery J, Harrison R, Reinisch F, et al. 2005. Work-related asthma among health care workers: surveillance data from California, Massachusetts, Michigan, and New Jersey, 1993-1997. Am J Ind Med 47(3): 265-275.
Preller L, Doekes G, Heederik D, Vermeulen R, Vogelzang PF, Boleij JS. 1996. Disinfectant use as a risk factor for atopic sensitization and symptoms consistent with asthma: an epidemiological study. Eur Respir J 9(7): 1407-1413.
Purohit A, Kopferschmitt-Kubler MC, Moreau C, Popin E, Blaumeiser M, Pauli G. 2000. Quaternary ammonium compounds and occupational asthma. International archives of occupational and environmental health 73(6): 423-427.
Sun HF, Hase T, Hata N, Kasahara I, Taguchi S. 2001. Extraction and separation of cationic surfactants from river sediments: application to a spectrophotometric determination of cationic surfactant in an aquatic environment using membrane filters. Anal Sci 17(11): 1291-1294.
Wong DA, Watson AB. 2001. Allergic contact dermatitis due to benzalkonium chloride in plaster of Paris. The Australasian journal of dermatology 42(1): 33-35.