New York State Department of Environmental Conservation Division of Solid & Hazardous Materials Bureau of Pesticides Management, 11 th Floor 625 Broadway, Albany, New York 12233-7254 Phone: 518-402-8788 FAX: 518-402-9024 Website: http://www.dec.state.ny.us/website/dshm/pesticid/pesticid.htm E-Mail: ppr@gw.dec.state.ny.us 1 July 22, 2005 CERTIFIED MAIL Ms. Jill Geyer SC Johnson & Son, Inc. 1525 Howe Street RETURN RECEIPT REQUESTED Racine, Wisconsin 53403-2236 Dear Ms. Geyer: Re: Registration with Conditions of the New Active Ingredient Picaridin Contained in the New Pesticide Products OFF! Skintastic IX Insect Repellent (EPA Reg. No. 4822-537), OFF! Skintastic X Insect Repellent (EPA Reg. No. 4822-536), and OFF! Skintastic XI Insect Repellent (EPA Reg. No. 4822-535) The New York State Department of Environmental Conservation (Department) has reviewed your application, received November 3, 2004, to register OFF! Skintastic IX Insect Repellent (EPA Reg. No. 4822-537), OFF! Skintastic X Insect Repellent (EPA Reg. No. 4822-536), and OFF! Skintastic XI Insect Repellent (EPA Reg. No. 4822-535). These products contain the new active ingredient picaridin (1-Methylpropyl 2-(2-hydroxyethyl)-1- piperidine carboxylate) (chemical code 070705). The application was deemed complete for purposes of review on February 23, 2005, and a registration decision is due by July 23, 2005. The above-referenced products are labeled for use as a dermally applied insect repellent for human use. The registration of this product is based on the technical review received from the New York State Department of Health (DOH) for impacts to human health. The three OFF! Skintastic products were not very acutely toxic to laboratory animals by the oral or dermal routes of exposure. The United States Environmental Protection Agency (USEPA) waived the acute inhalation toxicity study requirement for these products. This decision was based on the low toxicity of the active ingredient picaridin (also called KBR 3023 Technical) in the inhalation study and on the fact that the USEPA considered the inert ingredients of these three formulated products unlikely to increase their toxicity. On an acute basis, the OFF! Skintastic products were not irritating to the skin (tested on rabbits) nor were they dermal sensitizers (tested on guinea pigs). For all the above-described acute toxicity studies, except for the eye irritation studies (see below), the USEPA bridged the data on
2 formulations containing 20% picaridin to formulations containing either 5% picaridin (OFF! Skintastic X and XI Insect Repellents) or 10% picaridin (OFF! Skintastic IX Insect Repellent). The eye irritation studies conducted on these three OFF! Skintastic products showed that all three products caused moderate eye irritation (tested on rabbits). The Department recently reviewed the active ingredient picaridin as a manufacturing use only product (see final product label and letter at http://132.236.168.120/ppds/501549.tif). In that review, the DOH indicated that on an acute basis, picaridin was not very toxic. This chemical was neither a skin irritant (tested on rabbits) nor a skin sensitizer (tested on guinea pigs). It, however, was moderately irritating to the eyes (tested on rabbits). Picaridin caused some liver and kidney effects in subchronic dermal testing of laboratory animals, but at relatively high doses, as well as some dermal irritation. This chemical did not demonstrate neurotoxicity, developmental/reproductive toxicity, genotoxicity or evidence of carcinogenicity in laboratory animal studies. The USEPA classified picaridin as not likely to be a carcinogen. The USEPA conducted a human health risk assessment for the dermal application of picaridin to children and adults. Margins of exposure (MOEs) were determined for exposures to insect repellents containing this active ingredient at concentrations of 5% and 10%. For both adults and children, the application rate was assumed to be 1 milligram of product per square centimeter (mg/cm 2 ) of skin. It also was assumed that the application area was 25% of the total body surface area, which for an adult and a three-year old child were about 4,500 cm 2 and 1,640 cm 2, respectively. To estimate MOEs, calculated dermal exposure doses were compared to a noobserved-effect level (NOEL) of 200 milligrams per kilogram body weight per day (mg/kg/day). A NOEL of 200 mg/kg/day for systemic effects following dermal exposures was reported in the rabbit developmental toxicity study, the 90-day toxicity study in rats and the chronic/carcinogenicity study in rats. Because dermal absorption studies in rats and humans showed a marked species difference in absorption of picaridin (19.1% mean value in male rats versus 1.66% mean value in adult male humans), the dermal NOEL of 200 mg/kg/day in rats was adjusted to 2,300 mg/kg/day to account for the 11.5-fold difference in absorption. The estimated MOEs for three daily dermal applications of insect repellent products containing 5% picaridin were 240 and 140 for adults and children (three years old), respectively, whereas for products containing 10% of this active ingredient, the respective MOEs were 120 and 70. For two daily applications of a 10% product, the respective MOEs were 180 and 110. MOEs of 100-fold or greater are generally considered by the USEPA to provide adequate protection of the general public from noncancer effects. The USEPA also estimated MOEs for children orally exposed to picaridin through incidental hand-to-mouth contact, since some of the picaridin-containing product from treated areas of the skin may be transferred to the hands of children and subsequent hand-to-mouth ingestion may occur. The estimated MOEs from products containing 5% picaridin ranged from 930 to 9,200 and for 10%, the MOE range was from 460 to 4,600. The registrant contends that repeated hand-to-mouth contact is unlikely as the formulations contain a bittering agent to mitigate ingestion exposures. The labels for all three products contain the statement Do not apply more than three times per day. The OFF! Skintastic IX product (containing 10% picaridin) also states [O]n young children, do not apply more than twice in a day. This label does not define what ages are considered to be young children. Based on the USEPA human health risk assessment discussed above, three-year olds were apparently chosen to represent young children for the
3 purpose of estimating risks and defining label use statements. However, it is possible that some parents may apply these repellents to children younger than three years of age, and risks to this group should also be considered. Using the same methodology that USEPA used to calculate risks to adults and three-year old children, risks for children under the age of three can be estimated. For example, if one assumes that a child one year of age weighs 11.3 kg and that 25% of their skin surface area (1,236 cm 2 linearly scaled from the value use by USEPA for a 15 kg three-year old) is coated with repellent, exposure to one application of the 5% and the 10% formulation would be about 5.5 and 11.0 mg/kg/day, respectively. Comparing these doses to the NOEL of 200 mg/kg/day from the dermal developmental toxicity study in rats (adjusted by a factor of 11.5 to account for species differences in dermal absorption) yields MOEs of about 420 and 210 for one application of the 5% product and 10% product, respectively, for a child oneyear old. Thus, MOEs for two applications would be 210 and 105 for the 5% and 10% product, respectively. Using this same proportionality for a six- to 11-month old child, an MOE of 105 can also be calculated for two applications of the 10% product. However, the surface area to body weight ratio is slightly higher in children under one compared to that of a three-year old child. Assuming a 10% greater surface area to body weight ratio in these younger children, an MOE of about 96 can be calculated for two applications of the 10% product. Using specific body weight and surface area data from another source (National Research Council), MOEs of 100, 105 and 107 can be calculated for two applications of the 10% product on children one-half year, one year and two years of age, respectively. The potential for picaridin to cause dermal effects has been evaluated in both humans and laboratory animals. In the primary dermal irritation study, a one-time application of about 80 mg picaridin/cm 2 did not cause dermal irritation in rabbits. However, dermal effects (scabs, red foci and exfoliation) occurred in all dose groups including the lowest level of 80 mg/kg/day in the subchronic dermal exposure study in rats (the average dermal application rates in the 80 mg/kg/day group equaled about 1.3 and 1.7 mg picaridin/cm 2 in female and male rats, respectively). In the chronic studies, no gross dermal effects were noted in dogs, rats or mice. While some histological effects were noted in the skin of rats (acanthosis and hyperkeratosis) and mice (amyloid accumulation), these effects were attributed to the treatment methodology (i.e., continual skin contact with a fluid), not the picaridin. In humans, study summaries provided by the registrant indicate that neither a 20% aerosol product, a 20% lotion product nor a 100% picaridin caused dermal irritation when placed on the backs of test subjects at the rate of 50 mg/cm 2 and allowed to remain for a 48-hour period. The tests included either 30 (for the formulated products) or 50 (for the 100% material) human subjects, including some individuals with eczema, allergies and sensitive skin. Both positive (sodium lauryl sulphate solution) and negative (water) controls were run on these individuals, with the expected results indicating adequate test methodology. The registrant provided a number of efficacy studies on picaridin in the registration package. These studies were from various sources and contain varying degrees of detail. In these studies, picaridin generally provided similar or better repellency than DEET against mosquitoes in both field and laboratory studies. In terms of duration of protection, picaridin at a concentration of 15% provided complete protection from mosquito bites for about 4 to 7 hours in field and laboratory studies. Picaridin also provided protection from black flies and stable flies. One laboratory study in humans evaluated the efficacy of picaridin and DEET (both at 20% concentration) against black-legged ticks and found that picaridin provided complete protection for up to 2.5 hours, whereas DEET was not fully effective at 0.5 hours. No data on the efficacy of products containing either 5% or 10% picaridin against ticks were provided in the registration package. The originally submitted label for the Off! Skintastic IX product stated that it was
effective against ticks, but the registrant agreed to remove this statement from the label in light of our determination that the available efficacy data do not support this claim. 4 There are no chemical-specific federal or New York State drinking water/groundwater standards for picaridin. Based on its chemical structure, this compound falls under the 50 microgram per liter New York State drinking water standard for unspecified organic contaminants (10 NYCRR Part 5, Public Water Systems). The available information on the OFF! Skintastic products indicates that none was acutely toxic in laboratory animal studies. These products, however, were moderately irritating to the eyes. Accordingly, to mitigate adverse eye effects, each product label has the precautionary statement, [C]auses moderate eye irritation, and advises users to [A]void contact with eyes. While the active ingredient of these products, picaridin, also caused moderate eye irritation, it was shown not to be very acutely toxic. In addition, picaridin did not demonstrate neurotoxicity, developmental/reproductive toxicity, genotoxicity or carcinogenic properties. This chemical, however, caused some liver and kidney effects when dermally applied to laboratory animals in subchronic testing, but at relatively high doses. A human health risk assessment conducted by USEPA for the dermal application of picaridin indicated that this active ingredient can be applied at a concentration of 5% up to three times a day to both adults and children with MOEs 100-fold or above. This assessment also indicates that products containing 10% picaridin can be applied up to three times daily to adults and twice daily in children about three years old. Accordingly, the label for OFF! Skintastic IX Insect Repellent containing 10% picaridin instructs users not to exceed these numbers of applications. Similar calculations for children under three years old indicate that MOEs are also about 100-fold for two applications. Based on this analysis, the use of the Off! Skintastic products according to label directions would provide MOEs within the range considered by USEPA to provide adequate protection for the general public. However, the use of MOEs so derived to determine potential risks from the use of insect repellents containing picaridin presents several issues or uncertainties. First, the MOEs that were estimated are not large, particularly when repeat applications are made (in some cases the MOEs border 100-fold). Secondly, the health effects reported in the laboratory studies that form the basis of comparison in the risk assessment are not clear and consistent (e.g., the uncertain relevance of the kidney lesions for humans, and the inconsistency of liver effects in the various studies), which obscures determination of the relevant toxicity endpoint(s) and the dose levels at which they occur. Also, the adjustment factor based on mean values that was used to correct differences in dermal absorption between rats and humans adds another uncertainty that could shift the MOEs (the MOEs dictated the number of applications that USEPA allowed on the product labels). An influencing factor that USEPA did not include in its risk assessment is the effect that other ingredients in the product formulations may have on human dermal absorption. For example, dermal absorption in the human study was shown to more than double when 15% picaridin in ethanol was used in comparison to picaridin alone. Thus, the presence of this (ethanol is present in all three formulations at varying concentrations) and other ingredients in the products could influence absorption and the risk estimates. Moreover, some individuals may apply picaridin repellents to more than 25% of their body surface and at application rates greater than 1 mg/cm 2, which if considered would decrease the MOEs calculated in the risk assessment. Because people intentionally apply insect repellents directly to skin, there is significant potential for over application and either acute systemic effects or local effects such as eye or skin
5 irritation. The potential for these acute and local effects to occur cannot be easily evaluated from the data provided. Therefore, the products will be registered based on the condition of the subsequent submission of data that illustrate the types and numbers of adverse health effects associated with picaridin use in other countries and the U.S. The registrant, or a consortium of registrants who have registered picaridin-containing products, will be responsible for developing a tracking system in the U.S., possibly through the use of FIFRA 6(a)(2) reports or poison control center information databases. S.C. Johnson must contact the Department by December 1, 2005, to arrange a meeting to discuss options for developing a surveillance system. In summary, the Department has some concerns for the potential health effects that could occur from the use of picaridin-containing insect repellents, and believe there are uncertainties in the risk assessment conducted by USEPA. Nevertheless, picaridin does provide a public health benefit in that it appears to be efficacious against mosquitoes and biting flies, some of which can be disease vectors. The labels for the Off! Skintastic products also provide good precautionary statements and directions for proper use. Based on the above-mentioned information, the Department hereby accepts OFF! Skintastic IX Insect Repellent (EPA Reg. No. 4822-537), OFF! Skintastic X Insect Repellent (EPA Reg. No. 4822-536), and OFF! Skintastic XI Insect Repellent (EPA Reg. No. 4822-535) for general use registration with the following conditions: 1. The registrant (preferably in coordination with other registrants who may sell picaridin end use products in New York State) must develop a system for providing the Department with information on any adverse reactions among humans, as described above, by March 31, 2006. 2. All registrants of USEPA registered picaridin products must submit copies of any adverse effects notifications submitted to the USEPA in accordance with FIFRA 6(a)(2) to the Department regardless of New York State registration status. 3. The Department and the New York State Department of Health will closely monitor and review any picaridin adverse effect reports. The Department will react quickly and pursue mitigative measures deemed necessary in order to protect the health of the residents of New York State. 4. The continued registration of the three above-mentioned picaridin products and all subsequently registered picaridin products in New York State will be dependent upon the development of an acceptable tracking system and the submission of all adverse reaction reports to the Department. Enclosed are your Certificate of Pesticide Registration and New York State stamped ACCEPTED labels. The S.C. Johnson Corporation is reminded that if New York State registration is requested for any of these products, or any other picaridin product, which contain an expansion of use patterns or potentially increase exposure, the product will be considered a Major Change in Labeling and the Department will require an extensive review.
6 If you have any questions, please contact Samuel Jackling, Chief of our Pesticide Product Registration Section, at (518) 402-8768. Enclosures Sincerely, Maureen P Serafini Maureen P. Serafini Director Bureau of Pesticides Management cc: w/enc. - N. Kim/D. Luttinger, NYSDOH J. Kaplan/R. Mcfee, NYSDOH G. Good/W. Smith, Cornell University, PMEP