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didecyl dimethyl ammonium chloride
NYS DEC Letter - Registration of Major Change in Label 7/03

New York State Department of Environmental Conservation
Division of Solid and Hazardous Materials

Bureau of Pesticides Management, 9th Floor
625 Broadway, Albany, New York 12233-7254
Phone: (518) 402-8788     FAX: (518) 402-9024
Website: www.dec.state.ny.us

July 8, 2003

CERTIFIED MAIL
RETURN RECEIPT REOUESTED


Ms. Teresa C. Moore
Regulatory Affairs
The Procter & Gamble Company
11530 Reed Hartman Highway Cincinnati, OH 45241

Dear Ms. Moore:

RE: Registration of the Major Change in Label for the Active Ingredient Didecyl Dimethyl Ammonium Chloride Contained in Febreze Antimicrobial (EPA Reg. No. 3573-69)

   The New York State Department of Environmental Conservation (Department) has reviewed your application, received June 25, 2002, and additional information received October 18, 2002, January 10, 2003 and June 9, 2003, to register Febreze Antimicrobial (EPA Reg. No. 3573-69) which represents a Major Change in Label for the Active Ingredient Didecyl Dimethyl Ammonium Chloride (DDAC).

   This application was declared complete for purposes of review on January 27, 2003. This active ingredient was previously registered for use in New York State to disinfect hard, inanimate non-porous surfaces. Proctor & Gamble applied to register Febreze Antimicrobial, containing 0.13% of the active ingredient Didecyl Dimethyl Ammonium Chloride, for residential use on fabrics to kill bacteria that causes odors. The container is held 6-8 inches from the fabric, and the product is sprayed evenly over the fabric until damp, then allowed to dry completely. It is not recommended for use on leather or suede, and may cause spots on fabrics which are vulnerable to water spots, such as silk. The Department has reviewed the information supplied to date in support of registration of Febreze Antimicrobial (EPA Reg. No. 3573-69) in New York State.

   The New York State Department of Health (DOH) stated that the Febreze Antimicrobial product was not very acutely toxic by the oral, dermal or inhalation routes of exposure. DDAC, while also not very acutely toxic by dermal exposure, was moderately toxic by acute oral and inhalation exposures. The active ingredient also was a severe eye and skin irritant and showed slight skin sensitization properties. By contrast, the Febreze product caused only mild skin and eye irritation and was not a skin sensitizer.

   In a 90-day rat dermal toxicity study with DDAC, no systemic toxicity was observed at the highest dose tested, 12 milligrams per kilogram body weight per day (mg/kg/day). Dermal irritation in males, however, was reported at 6 mg/kg/day; the no-observed-effect level (NOEL) was 2 mg/kg/day. In females, dermal irritation was reported in all dose groups, including the lowest dose tested, 2 mg/kg/day. A 21-day rat dermal toxicity study on a diluted DDAC formulation reported no skin irritation or treatment-related effects other than a reduction in hindlimb grip strength in females at 500 mg/kg/day; the NOEL was 100 mg/kg/day.    DDAC caused some toxicity in chronic animal feeding studies. In a chronic feeding/oncogenicity study in mice, DDAC caused a reduction in mean body weights and body weight gain at 155.5 mg/kg/day and 193.1 mg/kg/day for males and females, respectively; the respective NOELS were 76.3 and 93.1 mg/kg/day. In rats chronically fed DDAC, an increased incidence of blood-related conditions (sinusoidal blood, hemosiderosis and histiocytosis) in the mesenteric lymph nodes was reported at 64 and 83 mg/kg/day in males and females, respectively; the respective NOELS were 32 and 41 mg/kg/day. In a one-year dog study, decreased cholesterol levels were reported in females at 20 mg/kg/day; the NOEL was 10 mg/kg/day. The U.S. Environmental Protection Agency (U.S. EPA) Office of Pesticide Programs established a reference dose (RD) of 0.1 mg/kg/day based on the NOEL of 10 mg/kg/day in the one-year dog feeding study and an uncertainty factor of 100. This RfD has not yet been adopted by the U.S. EPA's Integrated Risk Information System (IRIS)

   DDAC caused some developmental toxicity in the offspring of pregnant rats and rabbits, but only at doses that also caused maternal toxicity. In a rat developmental toxicity study, an increased incidence of skeletal variations was observed at 20 mg/kg/day; the NOEL was 10 mg/kg/day. Maternal toxicity, characterized by labored breathing and a reduction in body weight gain occurred at 10 mg/kg/day; the NOEL was 1 mg/kg/day. In rabbits, reduced fetal body weights and increased fetal mortality were reported at 10 mg/kg/day; the NOEL was 3 mg/kg/day. Maternal toxicity (reduction in body weight gain, hypoactivity and labored breathing) was reported at 3 mg/kg/day; the NOEL was 1 mg/kg/day. In a two-generation reproduction study in rats, a decrease in rat pup body weight, body weight gain and food consumption occurred at a dose of 113 mg/kg/day; the NOEL was 56 mg/kg/day. Parental toxicity characterized by a decrease in body weight, body weight gain and food consumption also occurred at 113 mg/kg/day with a NOEL of 56 mg/kg/day.

   No oncogenic effects were reported in either the chronic rat or mouse studies, and DDAC was negative in several genotoxicity studies. Based on these studies, the U.S. EPA classified DDAC as "not likely" to be carcinogenic in humans.

   The U.S. EPA conducted a health risk assessment for residential applicators and post-application exposures to Febreze Antimicrobial. For applicators using the product on carpets, furniture upholstery and mattresses, margins of exposure (MOEs) for dermal and inhalation exposure to DDAC were 1,000 and 1,400,000, respectively. For post-application exposures to DDAC residues, estimated MOEs from dermal contact with treated surfaces by children and adults were 7 and 81, respectively. For children's direct oral contact and hand-to-mouth contact, the respective MOEs were 950 and 460. Generally, the U.S. EPA considers MOEs of 100-fold or greater to provide adequate protection and the MOEs for post-application dermal exposure scenarios (MOEs of 7 and 81) were not considered acceptable. The NOEL used for estimating MOEs from dermal exposure was 2 mg/kg/day from the 90-day rat dermal toxicity study (the U.S. EPA review of the study, however, considered this dose level to be a lowest-observed-effect level for females).

   The potential for dermal effects from the direct transfer of DDAC residues on surfaces treated with the Febreze product to skin of residents can be evaluated in another manner. The dermal application rate for the 2 mg/kg/day dose level in the rat study is equal to about 0.013 mg DDAC/square centimeter. In their dermal exposure assessment, U.S. EPA assumed an application rate for the Febreze product on target fabrics to be equivalent to about 0.001 mg DDAC/square centimeter. Based on these calculations, the application rate for Febreze is only about 13-fold lower than the experimental application rate shown to cause dermal irritation in the 90-day rat study. This comparison, however, does not account for factors that distinguish experimental contact with DDAC from the contact which is likely to result from normal product use, principally that experimental contacts are repeated daily and involve occlusion by bandages. Other factors for which no data were provided include: the frequency and duration of dermal contact with treated surfaces in a home, dislodgeability of DDAC residues from treated surfaces, and the potential increased risk of dermal reactions from repeated product use on fabric surfaces.

   During the data completeness review of this product, the Department expressed concerns about the recent increase in marketing and availability of home-use products that contain antimicrobial active ingredients, such as Febreze Antimicrobial. To address these concerns, we requested that the registrant provide information on: the nature of microorganisms on fabrics; potential antibiotic/antimicrobial resistance development to this and other antimicrobial active ingredients; and information on the comparative efficacy of the Febreze product versus other similar products not containing antimicrobials. The registrant responded with some information on the presence of microorganisms in the home setting. The registrant also provided summary information on the efficacy of the Febreze Antimicrobial product against specific bacteria on fabrics. These summaries indicate that the Febreze Antimicrobial product reduced bacteria populations to a greater extent than the regular strength Febreze product. The registrant did not provide any information on potential antimicrobial/antibiotic resistance development from Febreze, or other similar products. However, information from the open literature indicates that this is an unresolved issue that is an active area of research.

   There are no chemical specific federal or State drinking water/groundwater standards for DDAC. Based on its chemical structure DDAC falls under the 50 microgram per liter general New York State drinking water standard for an "unspecified organic contaminant" (10 NYCRR Part 5, Public Water Systems).

   The available data indicate that Febreze Antimicrobial is not very acutely toxic nor does it cause significant dermal or eye irritation following single exposures. This product also is not a skin sensitizer. The active ingredient, DDAC, produced some toxicity in chronic animal studies, but did not cause reproductive, oncogenic or genotoxic effects, and produced developmental effects only at doses that also caused maternal effects. DDAC, however, is a severe skin and eye irritant and caused dermal irritation at relatively low application rates to skin in a 90-day rat study. In the health risk assessment conducted by the U.S. EPA, post-application dermal exposures were determined to pose unacceptable risks. Subsequent to this health risk assessment, and as a condition of federal registration (the conditional registration expired on January 31, 2003), the registrant conducted a 21-day dermal toxicity study on a formulated DDAC product. The Department did not receive any information on how the results of this study affected U.S. EPA's assessment of the risks posed by the Febreze product. Consequently, we requested that the registrant provide a thorough technical explanation of how the issue of unacceptable post-application dermal exposures was resolved with the U.S. EPA, or otherwise demonstrate why these exposures are not a concern, prior to allowing this product's registration in New York State.

   In response to our request, the registrant submitted information intended to modify the exposure assessment for DDAC from Febreze-treated fabric. Among this information was a study on in vitro penetration of DDAC through human skin. This study demonstrated that 2.92 percent of the applied DDAC was absorbed by the skin over a 24-hour period, with 0.06 percent of DDAC penetrating to the assay receptor fluid. The DDAC in the receptor fluid represents the material that is available for systemic circulation. The U.S. EPA in their health risk assessment of post-application dermal exposures to DDAC residues assumed a default dermal absorption factor of 100. The reassessment submitted by the registrant contends that if the MOEs are modified to account for this dermal absorption/penetration, the MOEs increase about 1,000-fold to acceptable levels. This position, however, is problematic in that the study U.S. EPA used in their exposure assessment was a 90-day dermal study in rats that had dermal irritation as a toxicity endpoint. Because the route of exposure was dermal, the assessment should not be modified to account for dermal absorption as might be done when extrapolating from effects by another route of exposure (e.g., ingestion or inhalation). It would be appropriate, however, to modify the estimates to account for interspecies differences in dermal absorption between rats and humans. While the registrant did not provide information on this aspect, it is generally believed that dermal absorption in the rat (and rabbit) exceeds that of humans, perhaps by several-fold.

   Since the development of the U.S. EPA's risk assessment, the registrant conducted a 21-day dermal toxicity study in rats using the formulated product. No dermal irritation effects were noted in this study at DDAC doses up to 1.3 milligrams per kilogram body weight per day (mg/kg/day). A decrease in hindlimb grip strength was reported at a dose level of 0.65 mg DDAC/kg/day, but the registrant concluded that these results were not treatment related given the absence of other neurological effects in this study. In the 90-day dermal toxicity study, no systemic effects were reported at doses up to 12.0 mg DDAC/kg/day, but dermal irritation was noted in females at 2.0 mg DDAC/kg/day. Based on the results of these two studies, a reasonable no-observed-effect level (NOEL) for dermal irritation in rats would be 1.3 mg DDAC/kg/day. Comparing the dermal exposure estimates from U.S. EPA (0.0245 mg/kg/day and 0.285 mg/kg/day for adults and children, respectively), MOEs of 53 and 5 can be calculated. These MOEs are slightly less than those calculated by U.S. EPA due to the somewhat lower NOEL used in this calculation. If the assessment accounts for interspecies differences in dermal absorption (assuming a 3-fold greater absorption by rats), the modified MOEs would then be about 160 and 15 for adults and children, respectively.

   The potential for the Febreze product to cause dermal irritation in humans can also be evaluated in another manner. Based on the information from the 90-day dermal rat study using technical grade DDAC, mild skin irritation was noted at an application rate of 12 micrograms per square centimeter skin (ug/cm2). Details of the 21-day dermal study in rats were not available, but assuming that the application methods were the same as the 90-day study, the corresponding DDAC application rate would be 7.8 ug/cm2. This application rate did not cause dermal irritation in test animals. In the acute dermal irritation study in rabbits, application of the formulated product at a rate of 100 ug DDAC/cm2 (four hours of exposure on shaved and occluded skin) caused mild skin irritation that resolved within 24 hours post application. The U.S. EPA exposure assessment estimated that dermal retention of DDAC residues from wet fabrics treated with Febreze would be 2.6 ug/cm2. For the purpose of evaluating consumer contact with freshly-treated fabrics, the acute dermal study in rabbits may provide the most applicable data. The application rate in this study was about 40-fold higher than the U.S. EPA estimated dermal retention of DDAC in adults and children. Because the dermal absorption of DDAC in rabbits is likely to be several-fold greater than human absorption, the DDAC available for causing dermal irritation in humans is likely to be correspondingly decreased. Also, the modifying factors discussed in the next two paragraphs would apply to this evaluation.

   Another factor that the registrant indicates should be considered in the exposure assessment is the transfer of residues to skin in contact with Febreze-treated surfaces. In support of this position, the registrant submitted a study that evaluated the transfer of hepta- and octachlorinated dibenzo-p-dioxins and dibenzofurans from fabrics to the stratum corneum (the outermost layer of skin) of human subjects in vivo. The study did not evaluate dermal absorption. This study reports that fabric left in contact with the backs of individuals for a period of eight hours resulted in the transfer of between one and five percent of the residues present in the material for those compounds tested. The registrant did not provide any information on whether these dibenzo-p-dioxins and dibenzofurans are reasonable surrogates for evaluating DDAC. Nevertheless, the transfer of DDAC residues from treated fabrics is likely to be less than 100 percent.

   In addition to the above issues, several other factors should be considered during an evaluation of exposure to DDAC from treated fabrics. The Febreze product is sprayed onto fabrics and the label indicates that fabrics should be allowed to dry prior to being reused. This should decrease the amount of residues that are likely to be transferred to skin. In addition, the dermal exposure studies in rats involved the direct application of wet material under occlusive bandages to the shaven skin of rats, which maximizes dermal contact and absorption. Moreover, the dermal studies in rats involved repeated DDAC exposure for prolonged periods, which is not representative of likely human exposure. As a result, the exposure estimates calculated by U.S. EPA would most likely over estimate risks.

   DDAC caused some dermal irritation in acute and subchronic toxicity studies in laboratory animals. Even though some dermal irritation was noted in these studies, adequate MOEs are likely to exist when the lower estimated exposure level for humans, the interspecies difference in absorption and the other modifying factors are considered. Based on the information submitted by the registrant and our re-evaluation of likely exposures, we do not expect that use of this product will pose unreasonable risks to consumers. Given the above, the NYSDOH does not object to the registration of Febreze Antimicrobial in New York State. The Department concludes that Febreze Antimicrobial should not have an adverse effect on the health of workers or the general public of New York State when used as labeled. Therefore, the Department hereby accepts for registration the new product Febreze Antimicrobial (EPA Reg. No. 3573-69) in New York State. Enclosed are your New York State stamped "ACCEPTED" label and a copy of the Certificate of Registration.

   Proctor & Gamble is reminded that if New York State registration is requested for this product or for any other product which contains Didecyl Dimethyl Ammonium Chloride with an increased application rate and/or expanded use sites, the product will be considered a Major Change in Labeling and the Department will require an extensive review.

   If you have any questions, please contact Mr. Samuel Jackling, Chief of our Pesticide Product Registration Section, at (518) 402-8768.

Sincerely,

Maureen P. Serafini Director
Bureau of Pesticides Management

Enclosures
cc: w/enc. N. Kim/D. Luttinger - NYS Dept. of Health
R. Zimmerman/ R. Mungari - NYS Dept. of Ag. & Markets
G. Good/W. Smith - Cornell University, PMEP