Document ID: EPA-HQ-OPP-2012-0811-0017
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-04-08T04:00Z

OFFICE OF CHEMICAL SAFETY
AND POLLUTION PREVENTION
                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
              OFFICE OF CHEMICAL SAFETY
AND POLLUTION PREVENTION
                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460

MEMORANDUM

DATE:	April 4, 2014

SUBJECT:	Response to Public Comments on the Registration Review Preliminary Work Plan for Triclosan (PC Code 054901)

TO:	Registration Review Docket
	Docket Number: EPA-HQ-OPP-2012-0811
	www.regulations.gov

FROM:	Sandra O'Neill, Chemical Review Manager
      Rose Kyprianou, Acting Team Leader
		Regulatory Management Branch II
            Antimicrobials Division
            
            Donna Randall, Senior Ecological Biologist
            Timothy Leighton, Senior Human Health Scientist
            Timothy McMahon, Senior Toxicologist
            Patricia Jennings, Senior Environmental Engineer
            James Breithaupt, Agronomist
            Srinivas Gowda, Microbiologist
            Risk Assessment and Science Support Branch
            Antimicrobials Division

THROUGH:	Lance Wormell, Branch Chief
      Regulatory Management Branch II
            Antimicrobials Division 
            
On March 27, 2013 EPA opened a 60-day public comment period on the preliminary work plan
(PWP) for the registration review of triclosan (Federal Register Notice 2013-07076). The comment period ended on May 28, 2013.  During the public comment period the agency received more than 150 comments. Comments received resulted in a modification to the anticipated data needs in the Triclosan Preliminary Work Plan (PWP).  The anticipated data needs in the Triclosan PWP were modified for the following reasons: (1) open literature reviews were completed for some biotic metabolism fate studies resulting in removal of these data requirements; (2) waivers were submitted for two fate data requirements and were accepted as meeting data requirements for these; and (3) the 850.3300 (or OECD 209) Activated Sludge, Inhibition Respiration (ASRI) study was added as an anticipated data requirement to support registration review of the textile/fabric use pattern.

Most comments were received from clean water agencies and clean water advisory boards voicing concerns about the EPA's approach to risk assessments for triclosan. These clean water organizations also made suggestions for refinements. These commenters were the Bay Area Clean Water Agencies (BACWA), the Central Valley Regional Water Quality Control Board, the San Francisco Bay Regional Water Quality Control Board, the California Stormwater Quality Association (CASQA), the Hampton Roads Sanitation District (HRSD), the National Association of Clean Water Agencies (NACWA), and Tri-Tac.

Vivimed Labs - a triclosan manufacturer, the Colgate Palmolive Company, and several other interested stakeholders also provided comments during the public comment period.  

The purpose of this memorandum is to address these comments. The Antimicrobials Division (AD) generally uses an outline format to address the comments (with name of submitter, comment and AD response, in that order).  In several of the comments, the submitter's name is abbreviated (see Table 1).  The comments are often written verbatim while other times they are summarized.  Similar comments from one or more respondents are combined and paraphrased.

      As a result of public comments, AD has revised sections of the Triclosan PWP.  The main revisions include:
      
   1. Correction of the anticipated registration review schedule to Table 2 (Section I, comment 12).
   2. Added the 850.3300 (or OECD 209) ASRI as an anticipated data requirement to support registration review of the textile/fabric use pattern (Section I, comment 9).
   3. Clarified that EPA's aggregate assessment to account for exposure to triclosan to children under 6 years old will include the most up-to-date information provided the information complies with EPA's Rule on Protections for Subjects in Human Research Involving Pesticides in the Final Work Plan (FWP) Section 3.4 (Section II, comments 20 and 22).    
   4. Updated characterization of the ecotoxicity data that was available at the time of the 2008 RED in Section 4 (Section II, comment 41).
   5. Added discussion on triclosan degradates to Section 4.3 Exposure Analysis Plan (Section I, comment 5).
   6. Clarified the reasons that in the case of pesticidal material preservative uses of triclosan, the environmental exposure pathway consisting of leaching of triclosan from in-service use of these materials with subsequent releases to wastewater was identified as a low likelihood of contributing to environmental risks of concern (Section I, comment 8).
   7. Defined the term "PCE" in the work plan (Section II, comment 46).
   8. Changes were made to Table 7 and 10 and the Benthic Invertebrate subsection of Appendix C to clarify that chronic, spiked-sediment benthic invertebrate testing for two freshwater and one estuarine/marine species is already required under the post-RED DCI which is why they are not identified in Table 6 as additional anticipated data requirements for registration review (Section II, comment 4).
   9. Modified Section 4; Tables 11, 12, 23 and 24; and Appendices C, E, and D based on Section II, comment numbers 48-54.
   
Table 1.  Submitters of Comments on the "Triclosan Preliminary Work Plan"
(in alphabetical order)
Bay Area Clean Water Agencies (BACWA)
Beyond Pesticides (BP)
California Regional Water Quality Control Board, Central Valley Region (CRWQCB CVR)
California Regional Water Quality Control Board, San Francisco Bay Region (CRWQCB SFB)
California Stormwater Quality Association (CASQA)
Colgate Palmolive Company (Colgate)
ENVIRON
Hampton Roads Sanitation District (HRSD)
National Association of Clean Water Agencies (NACWA)
Tri-TAC
Vivimed
*One additional submission was submitted by a member of the public wishing to bring certain studies to the agency's attention (these references were already submitted by the other commenters).

This document is divided in two sections to address comments (Table 2).  Section I includes those comments that were similar in nature or shared in common by two or more submitters and the agency's responses to these.  Section II offers all remaining individual comments, not included in Section I, and the agency's responses to these.

Table 2. Organization of the Response to Comments to the "Triclosan Preliminary Workplan"
                                    Section
Section Name
                                   Page No.
                                       I
Common Comments from Multiple Submitters
                                       4
                                      II
Remaining Individual Comments by Submitter
                                      12

              Section I. Common Comments from Multiple Submitters

1. BACWA, CRWQCB CVR, CRWQCB SFB, HRSD, NACWA, Tri-TAC, 

   Comment: Urge coordinated efforts with FDA to develop environmental risk assessment approach that incorporates all uses of Triclosan: Submitters suggested that registration review should include a cumulative environmental risk assessment that incorporates all uses of Triclosan, including those regulated under the Federal Food, Drug and Cosmetic Act (FFDCA) by the Food and Drug Administration (FDA). Submitters stated that antibacterial hand soaps, dish detergents and toothpaste contribute to triclosan loading experienced at a wastewater treatment facility and that all uses combined may result in loadings that can cumulatively impact human health and the environment and therefore should be addressed together.
   
   AD Response: EPA continues to coordinate efforts on assessment of triclosan with FDA. The two agencies are reviewing the effects of triclosan from two different perspectives. EPA regulates the pesticidal uses of triclosan, which make up a small percentage of the overall triclosan use in the United States. Multiple consumer uses are regulated by the FDA, including the effects of triclosan when it is used by consumers on a regular basis in hand soaps and body washes. EPA's human health assessment includes an aggregate risk assessment of all uses due to the type of data available. EPA's environmental assessment will consider modeling and/or monitoring data of releases from pesticidal uses. In making a regulatory decision about the pesticidal uses, EPA can only take regulatory action to mitigate risks from the uses that are pesticidal. However, if EPA finds that there may be a risk from exposure to triclosan that arises from FDA-regulated uses, we will share that information with FDA and work with FDA, as appropriate. FDA is aware the EPA is concerned about the potential adverse environmental impacts of triclosan.

   
2.  BACWA, CASQA, CRWQCB SFB, NACWA 

   Comment: Each use of triclosan should be evaluated for potential to contribute to environmental exposure, lifecycle leaching data from manufacturers of triclosan-impregnated materials should be required: Submitters expressed concerns that products impregnated with triclosan that are used indoors and may be washed or rinsed, can potentially release triclosan to wastewater facilities, and ultimately release to aquatic and terrestrial environments. Submitters with these concerns believe that each use needs to be evaluated for its potential to contribute to environmental exposures. BACWA cited an example from the Triclosan PWP, "EPA includes leaching from textiles in its conceptual model, stating that it is deemed to have `low likelihood of contributing to risk'... we wonder how EPA has come to this conclusion. A 2011 study showed that half or more of the Triclosan in impregnated fabrics was washed out in the first ten washes."

   AD Response: Potential environmental exposure via this pathway was considered by the agency.  The agency clarified in Section 4.1 the reasons that in the case of pesticidal uses of triclosan, the exposure pathway consisting of leaching from in-service use of preserved materials with subsequent releases to wastewater was identified as having `low likelihood of contributing to risk'.  See response to comment #8 in Section I.

3.  BACWA, CASQA, CRWQCB SFB

   Comment: Consider the potential ecological impacts of different uses of Triclosan in ecological studies regardless of status of agricultural mulch and film registrations: Submitters requested that the second footnote on p. 18 be removed so that ecological studies are required regardless of the status of agricultural mulch and film registrations. Submitters further stated agricultural product registrations should not impact whether aquatic toxicity studies are completed since numerous other EPA-registered uses of triclosan can potentially enter either fresh or saltwater bodies via wastewater discharge.
   
   AD Response: There appears to be confusion over the meaning of the anticipated data requirement and use site designations in Table 6 of the FWP.  For a given data requirement, the data are anticipated as needed for each use site listed in the "Use Site(s) Triggering Anticipated Data Requirement".  If there are more than one use site listed, each use site is anticipated as requiring the designated data requirement to support a risk assessment for that use site.  If a use site is removed, and one or more use site(s) remain for a given data requirement, this data are still anticipated as required to support the risk assessment for the remaining use sites.  However, this also ensures that those data requirements which are specific for a given use site and are no longer relevant for conduct of a risk assessment are appropriately removed.  The ecological studies are still anticipated as required to conduct a risk assessment for both the textile/fabric and agricultural plastic/poly mulch/film use sites as indicated in the updated Table 6 in the FWP.

4.  BACWA, CASQA, CRWQCB CVR, CRWQCB SFB

   Comment: The agency should require acute or chronic toxicity studies for estuarine/marine benthic organisms: Submitters expressed concerns over the work plan not planning to require acute or chronic toxicity studies for estuarine/marine benthic organisms (p. 30 and p. 86). Submitters suggest that since triclosan is expected to sorb to sediment, effects on biota in the benthos should be further investigated and are surprised that EPA has determined that one supplemental study (Table 29, p. 85) which did not measure growth or reproduction rates would be sufficient to determine the risk of triclosan in benthos. Given that triclosan is expected to deposit and persist in aquatic sediments, effects on benthic biota should be fully studied (sediment toxicity testing should be performed with spiked sediments, rather than by adding triclosan to the overlying water). Commenters suggest conducting sediment toxicity studies with the freshwater macroinvertebrate, Hyalella azteca, as it is commonly used to evaluate aquatic toxicity for Clean Water Act purposes.
   
   AD Response: Chronic spiked-sediment toxicity data are being required as part of the post-RED DCI (see Table 7).  The data call-in issued subsequent to the triclosan RED (GDCI 054901-30197, Docket EPA-HQ-OPP-2007-0513-0066) requires three chronic reproduction, spiked-sediment toxicity studies, two for freshwater species (a midge and an amphipod (Hyalella azteca)) and one for an estuarine/marine amphipod.  In the FWP a footnote has been added to Table 7 reflecting the number and type of species that have been required.  Additionally, in Table 10, the estuarine/marine benthic toxicity endpoint is modified to reflect that sediment testing was only required under the post-RED DCI and is not anticipated to be required in registration review. This change is also made to the text in the Benthic Invertebrate subsection in Appendix C.  When chronic benthic exposure conditions are expected to exist, the acute tests (these are actually 10-day subchronic tests) are not used to conduct a risk assessment for benthic invertebrates and therefore acute testing is not required for triclosan.  The conditions for acute versus chronic sediment testing scheme are covered in 40 CFR § 158.2240.   
   
5.  BACWA, CASQA, CRWQCB SFB

   Comment: Request the identification of all major triclosan degradates and provide for assessment of the ecological risks of these major degradates: Submitters stated numerous listed uses beyond textile manufacturing plants have the potential for discharge to municipal wastewater facilities. The following assertions are made about methyl triclosan: it has been detected in many municipal wastewater discharges, is more persistent than triclosan, and has been found to accumulate in fish. Submitters request that EPA include identification of all major triclosan degradates and provide for assessment of the ecological risks associated with the principal degradates.
   
   AD Response: The agency believes it has considered these issues in the work plan.
   Regarding other materials preservative use sites beyond textile manufacturing plants having the potential for discharge to municipal wastewater facilities -- The agency agrees there are other materials preservative use sites other than textiles/fabrics that under the right in-service use conditions may result in leaching and transport of triclosan into wastewater treatment facilities (see comment #2 of Section I).  However as described in more detail in response to comment #8 in Section I, none of these materials preservatives, in the case of pesticidal triclosan, are expected to result in environmental concentrations of concern. 
   
   Regarding identification of major degradates -- The agency has identified in Appendix B the major degradates of triclosan from both submitted data which has been reviewed and tentatively from some literature that will be reviewed.  The agency acknowledges that it did not include some compounds which have been found to co-occur in environmental and effluent samples and in some cases in laboratory studies due to concern over potential confounding of byproducts and their degradates as degradates of triclosan. Different manufacturing methods of triclosan result in different byproducts, such as some processes result in dioxin impurities, others do not.  The agency is trying to be careful in its evaluation and identification of major degradates attributable to the registered triclosan manufacturing source(s) used in registered antimicrobial products so as not to address risk issues that do not exist for these sources.  Part of the agency's analysis plan for registration review as stated in the first paragraph of Appendix B includes consideration of additional fate data from the open literature during the risk assessment phase.  If this analysis changes the current list of major degradates this will be addressed in the risk assessment phase.  A paragraph explaining this will be included in the Section 4.3 Exposure Analysis Plan.  
   
   Regarding including methyl triclosan and other major degradates in the risk assessment -- The agency plans to follow a total toxic residue approach for triclosan (see paragraph 3 of Appendix B). Models will be used in which the agency assumes, unless information to the contrary is found or submitted, that the major degradates are at least as toxic as the parent, triclosan.  As an example, the screen discussed in comment #8 of Section I assumed no degradation of triclosan.  

6. BACWA, CASQA, CRWQCB CVR, CRWQCB SFB, Tri-TAC 

   Comment: Suggestion for risk assessment studies on aquatic organisms or use of data on relevant/acceptable open literature: In Appendix C, EPA highlights several studies that are necessary for the risk assessment, including: acute and chronic estuarine/marine fish and crustacean (p.74); acute estuarine/marine mollusk (p. 74); full lifecycle fish study to establish chronic reproduction effects (p.74); full lifecycle test for freshwater invertebrates (p. 76); chronic estuarine/marine fish and invertebrates (p. 85). Submitters request that the following studies be performed for both triclosan and methyl triclosan either through data requirements or by acceptable open literature to address data gaps:
   :: Acute and chronic freshwater fish
   :: Acute and chronic estuarine/marine fish
   :: Acute and chronic freshwater crustacean
   :: Acute and chronic estuarine/marine crustacean
   :: Acute and chronic freshwater mollusk
   :: Acute and chronic estuarine/marine mollusk
   :: Acute and chronic freshwater benthic invertebrate
   :: Acute and chronic estuarine/marine benthic invertebrate
   
   AD Response: As stated in Section 4.4 Effects Analysis Plan, the agency plans as part of the risk assessment phase of registration review to search for effects data for triclosan.  This open literature search includes a search for effects data for its major degradates; the analysis plan will clarify that the planned literature search and review includes the major degradates. At this time the agency does not anticipate requiring acute and chronic freshwater mollusk data or estuarine/marine chronic mollusk data for triclosan or its major degradates to support registration review.  Such testing is not typically required to perform the risk assessments conducted for pesticides, and is considered higher tier testing (special studies under 40 CFR Part 158.75).  These higher tier tests would only be required if the risks to mollusks needed to be refined to a greater degree, the agency will consider the need for such refinements during the risk assessment phase of registration review.  Acute benthic invertebrate data are not anticipated to be required at this time (see the agency's response to comment #4 of Section I).  At this time the agency has not changed its position that it does not need methyl triclosan effects data to conduct a risk assessment for the textile/fabric use site.  For the remaining listed endpoints identified by submitters, the agency did identify these as endpoints which will be used to perform the risk assessment in the registration review phase and has outlined how such information will be obtained.  

7.  BACWA, CRWQCB SFB

   Comment: Studies pertaining to endocrine disrupting effects of Triclosan upon aquatic and amphibian species should be included in the work plan: Submitters note that there are studies indicating that triclosan has endocrine disrupting effects in aquatic and amphibian species. In Appendix C, EPA has stated that lifecycle fish studies are needed for assessing potential endocrine disruption (pp. 74-75). Submitters urge EPA to acknowledge these studies in the work plan and specify in the work plan schedule that an endocrine disruptor screening data call-in and analysis will be conducted as part of the registration review. 
   
   AD Response: Any additional endocrine disruption information in the open literature found as part of the Effects Analysis Plan effort described in Section 4.4 over that already described in Appendix C will be taken into consideration during the risk assessment phase of registration review.  The agency believes it did acknowledge endocrine disruption concerns in the work plan as reflected by calling in fish life cycle testing to account for reproductive effects rather than lower tier fish early life stage testing.  Additionally, the agency acknowledged in the Section 5 Endocrine Disrupter Screening Program (EDSP) part of the work plan that additional tests may be required for triclosan as part of that program.  
   
8.  BACWA, CRWQCB SFB, HRSD, Tri-TAC

   Comment: Proposal for conducting Down-the-Drain modeling representative of loading to municipal wastewater plants: Submitters acknowledge that textile manufacturing plant wastewater plant release data has been considered, but indicate that the textile data are not representative of loading to municipal wastewater plants. Submitters are surprised to find that the work plan does not include any modeling or evaluation of the municipal wastewater pathway for releases to the environment and suggest EPA conduct Down-the-Drain modeling that is typical for discharges to municipal wastewater treatment facilities.
   
   AD Response:   EPA performed a screening level assessment to determine whether triclosan released to municipal wastewater treatment plants (WWTPs) from pesticidal in-service uses of materials treated with triclosan would be expected to lead to potential risks to aquatic organisms downstream of WWTPs.  This screening-level assessment assumes that: (1) the entire maximum annual consumption volume of pesticidal triclosan used to treat textiles is released to WWTPs; (2) removal of triclosan during wastewater treatment would be 80 percent based on sorption of triclosan to activated sludge; and (3) levels of concern would be based on measurement endpoints for aquatic organisms in Table 10.  This screening-level assessment demonstrates that even if the entire maximum annual consumption volume of pesticidal triclosan used to treat textiles was released to municipal WWTPs over a one-year period, there would be no potential risks to listed or non-listed aquatic organisms downstream of WWTPs.

9.  BACWA, CRWQCB SFB, HRSD, Tri-TAC

   Comment: Require sludge respiration inhibition test to clarify the impacts of triclosan on environment and wastewater treatment microorganisms (EPA OPPTS Guideline 850.6800): Submitters request a sludge respiration inhibition test to support the analysis of municipal wastewater treatment plan process interference so the agency can evaluate how wastewater treatment organisms may be affected by triclosan.
   
   AD Response:  The agency agrees and we will add the activated sludge respiration inhibition study (OCSPP 850.3300 or OECD 209 (Note the numbering for the final activated sludge respiration inhibition guideline was changed from that of the draft)) to the anticipated data requirements listed in Table 6.
   
10. BACWA, CRWQCB SFB, HRSD, Tri-TAC

   Comment: EPA should require field studies that identify the impacts to biosolids management options; develop a methodology that evaluates impacts of pesticides to biosolids land application when EFAST DtD module indicates pesticides would partition into biosolids; and require analyses of bioaccumulation and toxicity to microbes, worms, and other terrestrial invertebrates through toxicity tests: Submitters expressed concern over triclosan's impact on wastewater agencies' management options for biosolids, they state some portion of the triclosan released to wastewater treatment facilities is likely to partition to the solid phase. Submitters request EPA require field studies that identify the impacts, if any, to biosolids management options including land application, incineration and surface disposal. Additionally, submitters urge the Offices of Pesticide Programs (OPP), Water (Offices of Wastewater Management and Science and Technology), and Research and Development to together develop a methodology that evaluates potential impacts of pesticides to biosolids land application whenever the EFAST Down-The-Drain module assessments indicate that pesticides would partition into biosolids. They state the existing OPP guidelines for the study of chemicals in the terrestrial environment could be modified to address biosolids-amended soil systems. Submitters further request that the evaluation include an analysis of bioaccumulation, toxicity to microbes, and toxicity to worms and other terrestrial invertebrates, entailing requiring the registrant to conduct studies such as a soil microbial community toxicity test (OPPTS Guideline 850.3200) and an earthworm subchronic toxicity test (OPPTS Guideline 850.3100). Submitters note that such evaluations should focus on fate, transport, and toxicity factors specifically applicable to the biosolids matrix, and not merely done on pure chemical compounds or pot studies. 
   
   AD Response: AD appreciates these comments. Discharge of triclosan into the environment via effluent will be considered to the best degree possible in the assessment. The agency is actively evaluating and meeting with the Office of Water to determine the extent to which ecological risk from pesticides via land application of biosolids should be addressed in its forthcoming environmental fate and ecological risk assessments and by extension, any additional data that should be required.  
   
   
   
   
11. BACWA, BP, CRWQCB SFB 

   Comment: More research needed to look into triclosan derivatives that undergo phototransformation: Submitters expressed concern regarding the potential for triclosan in wastewater to produce dioxins. They note that while EPA states that phototransformation of triclosan results in dioxins that are not among the 17 congeners that have significant toxicity equivalents (TEQs), they state there is a need for more research regarding chlorinated Triclosan derivatives (CTDs) that undergo phototransformation.
   
   AD Response: The agency acknowledges that dioxins from triclosan can be formed from photodegradation; however, the agency's preliminary examination indicates the dioxins are not among the congeners of concern for humans or ecological receptors (for more information, see Appendix F in the FWP).  The agency will further evaluate the need for any dioxin-specific assessment from triclosan in the risk assessment.

12. BACWA, CASQA, CRWQCB SFB

   Comment: Request for clarification of two scheduled public comment periods in 2019 and 2020, and request for an extended 90 day period: Submitters highlight that many local governments and non-profit organizations are resource constrained and/or may require multiple levels of review. They request that the proposed schedule be amended to provide 90 days review time. Submitters also request clarification whether the two scheduled public comment periods in 2019 and 2020 are to review the completed risk assessments. 
   
   AD Response: The anticipated registration review schedule (Table 2), has been corrected in the FWP. The 30 day comment period was incorrectly identified in the PWP as the comment period for the proposed decision, scheduled for 2019. That 30 day comment period corresponds to the preliminary risk assessment, now correctly scheduled in the FWP for 2018. The 60 day comment period for the proposed decision has been corrected to begin in 2019. It is important for the agency to keep the registration review process on track, altering the timeline presents a resource burden for the agency and the agency notes the commenters will have years to advance preparation for the 2018 and 2019 comment periods. For these reasons, the agency encourages the commenters to plan their resources to accommodate the registration review schedule and reassess the need for comment extensions in 2018 as necessary.

13. CASQA, CRWQCB CVR, CRWQCB SFB

   Comment: Outdoor uses should be included in the conceptual model due to potential leaching: Submitters allege outdoor uses of triclosan, including playground and boating equipment, pose a risk to aquatic environments if triclosan leaches from these impregnated products and is discharged via runoff, or potentially directly to water bodies from boating equipment. Submitters ask that outdoor uses be included in the conceptual model to account for outdoor products leaching triclosan, eventually making it to storm drains and creeks. Specific refinements to the PWP are listed:
      a. Modify Figure 2, the Conceptual Model for Environmental Exposure (Preliminary Work Plan, p. 28), to account for sources of triclosan that can enter the environment in urban areas via leaching or degradation of outdoor products impregnated by triclosan, with subsequent transport from impervious surfaces through the storm drain system to receiving waters. Add a Stressor to the Conceptual Model diagram labeled, "Urban Outdoor Products", leading to a Source labeled "Leaching and Runoff via Storm Drain", leading to the existing Exposure Media, "Surface Water/Sediment".
      b. Modify the Exposure Analysis Plan (section 4.3.1 Aquatic and Terrestrial Wildlife Exposure Estimates, p. 31) to include additional exposure scenarios for "in-service use" from urban areas within the modeling approach.
      c. Account separately for water and sediment matrices in assessments of both exposure and effects for aquatic organisms.
   
    AD Response:  According to the 2004-2005 Kline Report around 120,000 pounds of triclosan are used annually for antimicrobial pesticidal uses; this makes up less than 1% of the overall annual production of triclosan in the U.S. of around 10 million pounds (Kline, 2005). As such, the contribution of triclosan from pesticidal uses that would lead to storm water releases is negligible relative to the releases from all non-pesticidal uses.  Consequently, the level of refinement requested by the commenters is not needed (See Table 5 for a list of all pesticidal uses of triclosan.)

14. CASQA, CRWQCB CVR , CRWQCB SFB

    Comment: Urban runoff and urban outdoor modeling:
      a. In the modeling parameters, account for the distinct physical characteristics of urban storm drainage conveyance systems, which rapidly convey water and pollutants from application sites to receiving waters.
      b. Calculate four-day rolling averages and number of exceedances of biological criteria (e.g., LC50) every three years in the analysis of the PRZM/EXAM modeling results, and include the four-day, 3-year exposure estimates when assessing risks to aquatic organisms. This is necessary to provide the ability to conduct an effects assessment that is consistent with Office of Water methods, in addition to the planned approach for estimating environmental concentrations and assessing environmental risks. (Water quality criteria developed by EPA to protect aquatic life under the Clean Water Act involve a four-day averaging period for chronic effects, with the criteria not to be exceeded more than once every three years.)"
      c. Cover the full life cycle of the products for triclosan-impregnated products that may be exposed to outdoor conditions, accounting for product aging and discarded products.
      
   AD Response: The contribution of triclosan from pesticidal uses that would lead to storm water releases is negligible relative to the releases from all non-pesticidal uses (see response to comment 13).  Consequently, the level of refinement requested by the commenters is not needed (See Table 5 for a list of all pesticidal uses of triclosan.)

15. BACWA, CASQA, CRWQCB CVR , CRWQCB SFB, NACWA, Tri-TAC

   Comment: Cumulative effects of multiple pesticides need consideration: Submitters indicate it is common for mixtures of pesticides to be present in the water and sediments of receiving waters and note that studies have demonstrated that pesticide mixtures contribute to toxicity in both water and sediments. Submitters recommend that EPA develop a protocol for quantitative assessment of cumulative impacts of pesticide mixtures, they state the mixtures can be a significant factor contributing to potential toxic effects of triclosan.
   
   AD Response: EPA agrees that exposure to mixtures of compounds may affect the overall toxicity of any chemical. However, a quantitative assessment of risks associated with mixtures requires extensive data. Currently EPA does not have adequate data and has not yet developed the methodology to quantitatively assess mixtures of chemicals in the environment. Therefore, a quantitative assessment of mixtures cannot be conducted at this time. 

   EPA has a long term goal to develop a quantitative approach including guidance on weight-of-evidence analysis for assessing risks of pesticides mixtures. In the interim, EPA intends to qualitatively discuss the potential for differential exposure and toxicity from mixtures of compounds.
   
   
            Section II.  Remaining Individual Comments by Submitter

               Submitter: Bay Area Clean Water Agencies (BACWA)

1. Comment: "We strongly disagree with EPA's statement that, "while the EPA uses may contribute to exposure in some localized areas with industrial sources, the main contributor is the personal care product uses in most areas without industrial sources" (p. 65). As noted previously, many household products containing Triclosan, such as mops, cutting boards, countertops, toilets, sponges and linens, through their routine use at home or the work place, have the potential to release Triclosan to the environment through washing and rinsing. It is EPA's responsibility to ensure that Triclosan uses will not result in exceedances of water quality standards, impacts to biosolids management options, nor interference with the microorganisms that are crucial for effective wastewater treatment."

   AD Response: As discussed in EPA's response to comment 8 in section 1, EPA's screening-level assessment to determine whether triclosan released to municipal WWTPs from pesticidal in-service uses of materials treated with triclosan would be expected to lead to potential risks to aquatic organisms downstream of WWTPs demonstrates that even if the entire maximum annual consumption volume of pesticidal triclosan used to treat articles was released to municipal WWTPs over a one-year period, there would be no potential risks to listed or non-listed aquatic organisms downstream of municipal WWTPs.  As mentioned in EPA's response to comment 10 in section 1, the agency is actively evaluating the extent to which ecological risk from triclosan via land application of biosolids should be addressed in its forthcoming environmental fate and ecological risk assessment and by extension, any additional data that should be required.
   
2. Comment: "The enclosed study by Anger et al. (2013) notes there is very little information regarding the TEQs for di- and tri-chlorodibenzyl-p-dioxins (CDDs). The same study also indicates that effluent-dominated water bodies may have higher Triclosan and CTD-derived dioxins because there is little or no dilution."
   
   AD Response: Thank you for submittal of this reference.  The agency will evaluate and take into consideration this information during the risk assessment phase of registration review. 
   
3. Comment: "Another study by Buth et al. (2010) states that, `The CTD-derived PCDDs possess higher toxicities than 2,8-dichlorodibenzo-p-dioxin, a previously identified photoproduct of TCS, due to their higher chlorine substitution in the lateral positions. The load of TCS- and CTD-derived PCDDs to United States surface waters is estimated to be between 46 and 92 g toxicity equivalent units per year.'"
   
   AD Response: Thank you for submittal of this reference.  The agency will evaluate and take into consideration this information during the risk assessment phase of registration review.
   
4. Comment: BACWA submitted the following voluntary studies:
      a. San Francisco Estuary Institute (2011), Contaminants of Emerging Concern in the San Francisco Estuary: Triclosan and Triclocarban.
      b. Pannu, M. W., G. S. Toor, et al. (2012), "Toxicity and bioaccumulation of biosolids-borne triclosan in food crops" Environmental Toxicology and Chemistry 31(9): 2130-2137.
   
   AD Response: AD appreciates the submitted publications; the studies will be evaluated for use in the risk assessment phase of registration review.
   

                       Submitter: Beyond Pesticides (BP)

5. Comment: "In 2011, a study published in the journal PLoS One identified a fatal outbreak of the bacterium P. aeruginosa in a hospital as coming from the contamination of triclosan soap dispensers, which acted as a continuous source of the bacterium."
   
   AD Response: EPA does not regulate soap products that contain triclosan.

6. Comment: "A recent study, published in the Proceedings of the National Academy of Sciences, finds that triclosan impairs the ability of isolated heart muscle cells and skeletal muscle fibers to contract. Specifically, in the presence of triclosan, normal communication between two proteins that function as calcium channels became impaired, causing skeletal and cardiac muscle failure. The study also saw diminished heart and skeletal muscle contractions in living animals. Mice had up to a 25 percent reduction in heart function measures within 20 minutes of exposure to the chemical. Additionally, fathead minnows exposed to triclosan in water for seven days had significantly reduced swimming activity compared to controls during both normal swimming and swim tests designed to imitate fish being threatened by a predator. These effects were also attributed to reduced muscle activity. The authors of this study coming out of the University of California, Davis say that their results present strong evidence that triclosan could have effects on animal and human health at current levels of exposure."
   
   AD Response: The submission of comments regarding the study is appreciated.  The agency will consider the study and the results presented in the study when the study is reviewed and at the time of the final human health risk assessment.
   
7. Comment: "2013 research discovered triclosan and several of its derivatives in sediment samples taken from freshwater lakes across Minnesota, including Lake Superior. Some of the breakdown products that scientists discovered were polychlorodibenzo-p-dioxins (PCDDs), a group of chemicals known to be toxic to both humans and wildlife. Its toxicity to several aquatic flora and fauna makes triclosan a threat to aquatic ecosystems."
   
   AD Response: The agency is carefully evaluating all available information connecting dioxin formation with triclosan.  The agency will reconsider the need for any dioxin-specific assessment from triclosan in the risk assessment phase of registration review if new information changes the current understanding. 
   
8. Comment: "Additionally, triclosan has not been demonstrated to be efficacious for the uses it is branded for (antimicrobial plastics and textiles), and as such, must be considered `misbranded.'"
   AD Response: There are no EPA registered triclosan products that bear public health claims. Although the EPA does not require the submission of efficacy data for non-public health products, per 40 CFR § 158.400 (e), "each registrant must ensure through testing that his product is efficacious when used in accordance with label directions and commonly accepted pest control practices."
9. Comment: Beyond Pesticides submitted a list of publications for consideration. 
      a. Relationship between urinary triclosan and paraben concentrations and serum thyroid measures in NHANES 2007-2008. [Koeppe ES, Ferguson KK, Colacino JA, Meeker JD.2013. Sci Total Environ;445-446:299-305]
      b. Octylphenol (OP) and triclosan, which have an estrogenic activity, were examined to find whether they can induce cell growth of human breast cancer cells. [Lee, H. Park, M. Yi, B & Choi, K. 2012. Endocrine Abstracts 29 P749]
      c. The Impact of Bisphenol A and Triclosan on Immune Parameters in the U.S. Population, NHANES 2003 - 2006 [Clayton, E Todd,M. Dowd,J and Aiello, A. 2011. Environ Health Perspect. 119(3): 390 - 396.]
      d. Effects of Triclocarban, Triclosan, and Methyl Triclosan on Thyroid Hormone Action and Stress in Frog and Mammalian Culture Systems. [Hinther, A. Bromba, C. et al. 2011. Environ. Sci. Technol., 45 (12); 5395 - 5402]
      e. Short-term Exposure to Triclosan Decreases Thyroxine In Vivo via Upregulation of Hepatic Catabolism in Young Long-Evans Rats. [Paul, K et al. 2010. Toxicol. Sci. 113 (2): 367-379.]
      f. Triclosan Exposure Modulates Estrogen-Dependent Responses in the Female Wistar Rat. [Stoker, T. et al. 2010. Toxicol. Sci. 117 (1): 45-53.]
      g. Some flame retardants and the antimicrobials triclosan and triclocarban enhance the androgenic activity in vitro [Christen V, Crettaz P, Oberli-Schrämmli A, Fent K. 2010. Chemosphere, 81(10):1245-52.]
      h. Triclosan has endocrine-disrupting effects in male western mosquitofish, Gambusia affinis [Raut SA and Angus RA. 2010. Environ Toxicol Chem; 29(6):1287-91.]
      i. Alteration of testicular steroidogenesis and histopathology of reproductive system in male rats treated with triclosan. [Kumar V. et al. 2009. Reprod Toxicol. 27(2):177-85.]
      j. Triclosan is a potent inhibitor of estradiol and estrone sulfonation in sheep placenta [James MO, et al. 2010. Environ Int. 36(8):942-9.]
      k. Evaluation of the endocrine disrupting potential of the antimicrobial triclosan on early embryonic and larval development in zebrafish [Good, R,K and Daggett, M. A. 2010. FASEB J. (Meeting Abstract Supplement) 1036.1]
      l. Triclosan Affects Thyroid Hormone - Dependent Metamorphosis in Anurans [Helbing, C., van Aggelen, G and Veldhoen, N. 2011. Toxicol. Sci.119 (2): 417-418]
      m. Maternal exposure to triclosan impairs thyroid homeostasis and female pubertal development in Wistar rat offspring [Rodríguez, P.E. and Sanchez, M.S. 2010. J Toxicol Environ Health A.;73(24):1678-88.]
      n. Triclosan exposure and allergic sensitization in Norwegian children [Bertelsen RJ, Longnecker MP, Lovik M, Calafat AM, et al. 2013. Allergy.68(1):84-91]
      o. Exposure to triclosan augments the allergic response to ovalbumin in a mouse model of asthma [Anderson SE, Franko J, Kashon ML, Anderson KL, Hubbs AF, Lukomska E, Meade BJ.2013. Toxicol Sci;132(1):96-106]
      p. Triclosan reduces the levels of global DNA methylation in HepG2 cells [Ma H, Zheng L, et al. 2013. Chemosphere. 2013 Jan;90(3):1023-9]
      q. Pulmonary toxicity screening of triclosan in rats after intratracheal instillation [Kwon JT, Yang YS, Kang MS, et al. 2013. J Toxicol Sci.;38(3):471-5.]
      r. Triclosan impairs excitation-contraction coupling and Ca2+ dynamics in striated muscle [Cherednichenko G, Zhang R, Bet al. 2012. Proc Natl Acad Sci;109(35):14158-63]
      s. Disruption of blastocyst implantation by triclosan in mice: impacts of repeated and acute doses and combination with bisphenol-A [Crawford BR, Decatanzaro D. 2012.Reprod Toxicol.34(4):607-13]
      t. Effects of triclosan on the normal intestinal microbiota and on susceptibility to experimental murine colitis [Pasch, E. et al. 2009. FASEB J. Meeting Abstract Supplement) 977.10.]
      u. The Impact of Bisphenol A and Triclosan on Immune Parameters in the US Population, NHANES 2003-2006 [Clayton EM, Todd M, Dowd JB, Aiello AE. 2010. Environ Health Perspect. doi:10.1289/ehp.1002883.]
      v. Triclosan exposure alters postembryonic development in a Pacific tree frog (Pseudacris regilla) Amphibian Metamorphosis Assay (TREEMA) [Marlatt VL, Veldhoen N, et al. 2013.Aquat Toxicol;126:85-94]
      w. Triclosan impairs swimming behavior and alters expression of excitation-contraction coupling proteins in fathead minnow (Pimephales promelas) [Fritsch EB, Connon RE, et al. 2013. Environ Sci Technol;47(4):2008-17]
      x. Assessing triclosan-induced ecological and trans-generational effects in natural phytoplankton communities: a trait-based field method [Pomati F, Nizzetto L. 2013. Ecotoxicology. doi:10.1007/s10646-013-1068-7]
      y. Triclosan occurrence in freshwater systems in the United States (1999-2012): A meta-analysis [Perez AL, De Sylor MA, Slocombe AJ, Lew MG, Unice KM, Donovan EP. 2013. Environ Toxicol Chem;32(7):1479-87]
      z. Occurrence and removal of emerging pharmaceutical, personal care compounds and caffeine tracer in municipal sewage treatment plant in Western Greece [Stamatis NK and Konstantinou IK. 2013. J Environ Sci Health B ;48(9):800-13]
      aa. Effect of wastewater chlorination on endocrine disruptor removal [Noutsopoulos C, et al. 2013. Water Sci Technol. 2013;67(7):1551-6.]
      bb. Triclosan inhibits arbuscular mycorrhizal colonization in three wetland plants [Twanabasu BR, Smith CM, et al. 2013.Sci Total Environ. 2013 Mar 1;447:450-7]
      cc. Triclosan enriches for Dehalococcoides-like Chloroflexi in anaerobic soil at environmentally relevant concentrations [Wang S, Wang X, Poon K, et al. 2013. Chemosphere. 2013 May 3. pii: S0045-6535(13)00531-6.]
      dd. Removal and reductive dechlorination of triclosan by Chlorella pyrenoidosa [Wang S, Wang X, Poon K, et al. 2013. Chemosphere. 2013 May 3. pii: S0045-6535(13)00531-6.]
      ee. In vitro effects of triclosan and methyl-triclosan on the marine gastropod Haliotis tuberculata [Gaume B, Bourgougnon N, et al. 2012. Comp Biochem Physiol C Toxicol Pharmacol. [Epub ahead of print]
      ff. Impairment of the bacterial biofilm stability by triclosan [Lubarsky HV, Gerbersdorf SU, et al. 2012. PLoS One. 2012;7(4):e31183.]
      gg. Toxicity and bioaccumulation of biosolids-borne triclosan in food crops [Pannu MW, Toor GS, O'Connor GA, Wilson PC. 2012. Environ Toxicol Chem.31(9):2130-7]
      hh. Occurrence of triclosan, triclocarban, and its lesser chlorinated congeners in Minnesota freshwater sediments collected near wastewater treatment plants [Venkatesan AK, Pycke BF,et al. 2012. J Hazard Mater;229-230:29-35]
      ii. Fate of triclosan in field soils receiving sewage sludge [Butler E, Whelan MJ et al. 2012. Environ Pollut.167C:101-109.]
      jj. Temporal trends of triclosan contamination in dated sediment cores from four urbanized estuaries: Evidence of preservation and accumulation [Cantwell. M.G. et al. 2010. Chemosphere 78(4); 347-352.]
      kk. Triclosan persistence through wastewater treatment plants and its potential toxic effects on river biofilms [Ricart, M. et al. 2010. Aquatic Toxicology, 100(4); 346-353.]
      ll. Potential biochemical and genetic toxicity of triclosan as an emerging pollutant on earthworms (Eisenia fetida) [Lin, D. et al. 2010. Chemosphere, 81(10);1328-1333.]
      mm. Dioxin Photoproducts of Triclosan and Its Chlorinated Derivatives in Sediment Cores [Buth, J et al. 2010. Environ. Sci. Technol., 44 (12), pp 4545 - 4551.]
      nn. Fate of triclosan in agricultural soils after biosolid applications [Lozano,M. et al. 2010. Chemosphere, 78(6); 760-766.]
      oo. Occurrence of triclosan in plasma of wild Atlantic bottlenose dolphins (Tursiops truncatus) and in their environment [Fair PA, et al. 2009. Environ Pollut;157(8-9):2248-54.]
      pp. Environmental Exposure of Aquatic and Terrestrial Biota to Triclosan and Triclocarban [Chalew, T and Halden, R. 2009. JAWRA. 45(1): 4 - 13.]
      qq. Occurrence, Fate, and Impact of Triclosan and Other Antimicrobials to Wastewater Treatment Utilities [Halden, R. and Katz, J. Proceedings of the Water Environment Federation, Microconstituents and Industrial Water Quality, pp. 511-517(7).]
      rr. Occurrence and loss over three years of 72 pharmaceuticals and personal care products from biosolids - soil mixtures in outdoor mesocosms  [Walters E, McClellan K, Halden RU. 2010. Water Res.;44(20):6011-20.]
      ss. Pharmaceuticals and personal care products in archived U.S. biosolids from the 2001 EPA national sewage sludge survey [McClellan K, and Halden RU. 2010. Water Res.; 44(2):658-68.]
      tt. Detection of the antimicrobials triclocarban and triclosan in agricultural soils following land application of municipal biosolids [Cha, J. and Cupples, AM. 2009. Water Res.;43(9):2522-30.]
      uu. Staphylococcus epidermidis Isolated in 1965 Are More Susceptible to Triclosan than Current Isolates [Skovgaard S, Nielsen LN, et al. 2013. PLoS One. 2013 Apr 16;8(4):e62197]
      vv. A novel resistance mechanism to triclosan that suggests horizontal gene transfer and demonstrates a potential selective pressure for reduced biocide susceptibility in clinical strains of Staphylococcus aureus. [Ciusa ML, Furi L, et al. 2012. Int J Antimicrob Agents.40(3):210-20]
      ww. Prevalence of decreased susceptibility to triclosan in Salmonella enterica isolates from animals and humans and association with multiple drug resistance [Copitch, J et al. 2010. Antimicrobial Agents. 36(3), 247-251.]
      xx. Structural basis of triclosan resistance [Jiten Singh N, et al. 2010. J Struct Biol. doi:10.1016/j.jsb.2010.11.008.]
      yy. Triclosan Derivatives: Towards Potent Inhibitors of Drug-Sensitive and Drug-Resistant Mycobacterium tuberculosis [Freundlich, J. et al. 2009. ChemMedChem 4(2):241 - 248.]
         
   AD Response: AD appreciates the list of suggested studies and will consider the relevance of these studies toward characterizing exposure and risk in the risk assessment phase of registration review. For the studies mentioned in bullets e and f above, AD has already considered those data as part of a case study during the "Integrated Approaches to Testing and Assessment strategies (IATA): Use of New Computational and Molecular Tools" FIFRA Scientific Advisory Panel (SAP) consultation in May, 2011. The studies mentioned in bullets e and f above will be taken into account during the comprehensive human health risk assessment that will be performed as part of the registration review of triclosan.

   
          Submitter: California Regional Water Quality Control Board,
                      Central Valley Region (CRWQCB CVR)

10. Comment: CRWQCB CVR voluntary submitted studies for the agency to consider.
      a. Conn KE, Lowe KS, Drewes JE, Hoppe-Jones C, Tucholke MB. 2010. Occurrence of pharmaceuticals and consumer product chemicals in raw wastewater and septic tank effluent from single-family homes. Environmental Engineering Science 27(4), 347-356.
      b. Davis EF, Klosterhaus SL, Stapleton HM. 2012. Measurement of flame retardants and triclosan in municipal sewage sludge and biosolids. Environment International 40, 1-7.
      c. Maruya KA, Vidai-Dorsch DE, Bay SM, Kwon JW, Xia K, Armbrust KL. 2012. Organic contaminants of emerging concern in sediments and flatfish collected near outfalls discharging treated wastewater effluent to the Southern California Bight. Environmental Toxicology and Chemistry 31(12), 2683-2688.
      d. Perron MM, Ho KT, Cantwell MG, Burgess RM, Pelletier MC. 2012. Effects of triclosan on marine benthic and epibenthic organisms. Environmental Toxicology and Chemistry 31 (8), 1861-1866.
      e. Svenningsen H, Henriksen T, Prieme A, Johnsen AR. 2011. Triclosan affects the microbial community in simulated sewage-drain-field soil and slows down xenobiotic degradation. Environmental Pollution 159, 1599-1605.
   
   AD Response: AD appreciates the list of suggested studies and will consider the relevance of these studies toward characterizing exposure and risk in the environmental risk assessment phase of registration review.
   
   
Submitter: California Regional Water Quality Control Board, San Francisco Bay Region  (CRWQCB SFB)
   
   
11. Comment: Recommendations for better modeling of municipal wastewater treatment plant releases. "To further improve the model, we encourage U.S. EPA to include better modeling of municipal wastewater treatment plants in the work plan through the recommendations detailed below.
   ::Add a stressor to Figure 1, the Conceptual Model for Environmental Exposure (p. 27), labeled "General Household & Workplace Products," leading to a source labeled "Leaching/Washing," leading to the exposure media, "Waste Water Treatment Plant (WWTP)." 
   :: Modify the Exposure Analysis Plan (p. 31, section 4.3.2) to include all uses that have the potential to release or leach triclosan down drains to wastewater facilities and the environment. 
   :: Conduct the Down-the-Drain modeling that is typical for discharges to municipal wastewater treatment facilities to accurately inform an environmental risk assessment. Integrate leaching studies into the process to estimate how much and how fast triclosan leaches from products."
   
   AD Response:  As discussed in EPA's response to comment 8 in section 1, EPA's screening-level assessment to determine whether triclosan released to municipal wastewater treatment plants (WWTPs) from pesticidal in-service uses of materials treated with triclosan would be expected to lead to potential risks to aquatic organisms downstream of WWTPs demonstrates that even if the entire maximum annual consumption volume of pesticidal triclosan used to treat textiles was released to municipal WWTPs over a one-year period, there would be no potential risks to listed or non-listed aquatic organisms downstream of municipal WWTPs.
   

         Submitter: California Stormwater Quality Association (CASQA)
                                       
   
12. Comment: "EPA has requested submittal of water quality monitoring data for triclosan (Preliminary Work Plan, p.35). CASQA agrees that monitoring data would be invaluable for registration review. We encourage EPA to require pesticide registrants to provide environmental monitoring data for products registered for uses in urban areas, and especially to acquire acquisition of such data in urban creeks (both water and sediment matrices)."
   
   AD Response: The agency believes the annual loading of triclosan available for leaching in urban areas from pesticidal uses is negligible and does not rise to a level of concern requiring monitoring in urban areas.  
   
                              Submitter: Colgate
   
   
13. Comment: "There is insufficient justification for advancing the registration review schedule for triclosan by 10 years." Colgate indicates the Preliminary Work Plan does not identify specific or new information that may change the registration decision EPA reached in 2008.
   
   AD Response: For the 2008 RED, NHANES data were available for triclosan only for the 2003-2004 survey cycle. Subsequently, the Center for Disease Control (CDC) has released the triclosan results for the 2005-2006, 2007-2008, and 2009-2010 survey years. Additional data on effects of triclosan on thyroid hormones and estrogen- related effects have also been made available from EPA's Office of Research and Development (ORD). ORD studies on the thyroid and estrogen effects led EPA to determine that more research on the potential health consequences of endocrine effects of triclosan is warranted. These data will be used for the registration review risk assessment of triclosan exposure. Once completed, EPA will post its revised assessment in the public docket, and revisit its regulatory decision, if the science supports a change.

   EPA is also collaborating closely on science and regulatory issues with the FDA, which is scheduled to issue a final monograph establishing conditions for use of consumer hand soap products containing triclosan. This joint effort will help to ensure government-wide consistency in the regulation of the chemical.
   
14. Comment: "EPA must base its review on sound science, consistent with the Administration's commitment `to ensure that federal policies are based on the best and most unbiased scientific information,' and EPA's commitment that its policies'must be grounded, at a fundamental level, in sound, high quality science.' Therefore, EPA's work plan and RED for triclosan should, at a minimum:            
      a.  use a "weight of the evidence" approach to evaluating data;
      b.  meet EPA's and the Office of Management and Budget's (`OMB') Information Quality Guidelines under the Data Quality Act, which requires EPA to use the best available, peer-reviewed science and supporting studies conducted in accordance with sound and objective scientific practices and to use data collected by accepted methods or the best available methods; and
      c.  evaluate and interpret data in a transparent and scientifically rigorous manner, including taking into account species differentiation, modes of action and non-linear dose-response reactions when evaluating toxicology, and basing exposure assumptions on the best and most recent data that are representative of actual exposure conditions."
         
   AD Response: The agency agrees with the statements above. EPA continues to review and evaluate registered pesticides as scientific methods and data continuously change over time and will use high quality science to reevaluate triclosan through the registration review program. The triclosan RED that was issued in 2008 represents the agency's regulatory determination as of the time issued. 

15. Comment: "EPA is reviewing the eligibility of triclosan to be registered as a pesticide under FIFRA. Accordingly, this review should focus on FIFRA-regulated uses, and avoid reaching or suggesting conclusions regarding uses of triclosan that are outside of EPA's jurisdiction and regulated by other authorities such as the FDA. The statutory criteria used by the FDA are not the same as the FIFRA pesticide review criteria, and it could cause significant confusion among the public and stakeholders if EPA suggested conclusions regarding FFDCA uses that differed from or conflicted with the conclusions reached by FDA."
   AD Response:  EPA has regulatory authority only over the pesticidal uses of triclosan and FDA has authority over the use of triclosan in personal care, over-the-counter drug, and some other types of household products. In making a regulatory decision about the pesticidal uses, EPA can only mitigate risks from the uses that are pesticidal. However, if EPA finds that there may be a risk from exposure to triclosan that arises from FDA-regulated uses, we will share that information with FDA and work with FDA, as appropriate. 

16. Comment: "Aggregate human exposures to triclosan should be evaluated using the 2009  -  2010 data set from the National Health and Nutrition Examination Survey ("NHANES") biological monitoring data collected by the Center for Disease Control and Prevention ("CDC"). In Section 3.4.1 of the Preliminary Work Plan, EPA discusses plans to conduct an aggregate human exposure assessment to account for exposure to triclosan from dietary and residential post-application exposures, including all post-application exposures to triclosan from both EPA and FDA regulated uses (which will thus over-state exposures from uses regulated by EPA under FIFRA). EPA states that it will use the results from the NHANES studies from 2005-06, 2007-08, 2009-10, as well as the 2003-04 surveys, but does not explain how it intends to use these data sets."

   AD Response: The NHANES results from the most recent survey at the time of the risk assessment will be used to estimate the potential aggregate exposure and risks associated with all of the triclosan uses.  It is not possible to separate out the contribution to aggregate exposure from EPA versus FDA regulated uses based on the NHANES sampling methodology.  The NHANES results from previous year surveys will also be included to characterize the trend in triclosan exposure.

17. Comment:  "The half-life of triclosan in the body is fairly short (~ 11 hours), making it important to adjust the spot urine samples collected in the NHANES data to a daily amount, as the concentration may vary over the day. There are several methods that can be used to accomplish this, including using creatinine concentrations and daily urinary volumes. EPA has used several methods in the past (EPA 2008, EPA 2011). However, the data and assumptions used by EPA in applying those methods are not transparent. In the 2008 RED, the procedures and assumptions used to convert the NHANES spot urine concentrations into doses were not described, but EPA did refer to Cohen (2008) as a source. However, Cohen (2008) is not publically available, so the method was not provided in the 2008 RED. In addition, the urine volumes (Geigy 1981) used by USEPA in the urinary volume adjustment method were also not provided in the 2008 RED. Since these methods are complex and require information from multiple sources, EPA must be transparent with the data and methods used for to evaluate NHANES data."
   
   AD Response: For transparency, EPA will include Cohen (2008) in the triclosan docket. The Geigy study is publicly available and is listed in the references section at the end of this memo.

18. Comment: "Based on the currently available data, adjustment relying on daily creatinine concentrations is recommended. NHANES provides creatinine concentration data for each individual in the survey with data on triclosan concentrations in urine. In addition, recent studies provide more current sources for adjustment of urinary data using creatinine (Mage 2004, 2007), rather than relying on Geigy (1981), which is based on data that is more than 3 decades old. The choice of the method should be based on a combination of the most recent data and one that accounts for the variability in the population, which is provided when using the creatinine adjustment method based on the NHANES survey results."
   
   AD Response: The triclosan 2008 RED used three conversion methods to convert the spot urine concentrations to a daily dose, including: (1) Mage et al (2007) with an obesity correction factor; (2) Schafer et al (2004) using actual body weights from subjects; and (3) Geigy (1981) values for both a mean and 95[th] percentile of daily urine excretion volume.  The 2008 RED also discussed the creatinine adjustments methods.  For transparency, EPA will include Cohen (2008) in the triclosan docket. The remaining studies are publicly available and they are listed in the references section at the end of this memo. 
    
19.  Comment: "The distribution of the NHANES data should be considered when calculating means and percentages of triclosan concentrations in urine. The NHANES data are more correctly described by a lognormal distribution than a normal distribution. An assumption of normality could over-state the mean and upper percentile values."
   
   AD Response: EPA did not make any assumptions about the distributions of the NHANES data (i.e., EPA did not assume normal nor lognormal distributions). Instead EPA used a non-parametric approach.  The CDCP's comprehensive "Fourth National Report on Human Exposure to Environmental Chemicals" and much of the scientific NHANES literature uses similar non-parametric methods to analyze the NHANES concentration data. 

20. Comment: "Although the aggregate exposures presented in the 2008 RED using the NHANES data were considered to represent population triclosan exposures from all sources, the NHANES data does not include exposures to children under the age of 6 years old. EPA states in the Preliminary Work Plan that it will conduct a separate estimate for children under 6 years old, but does not describe how that separate assessment will be conducted. The Work Plan must describe with transparency the method and data EPA intends to use. An effort should be made to obtain any relevant and scientifically valid biomonitoring data that can be located for children under the age of 6 for evaluating aggregate exposure. The combination of the published literature relied upon by Health Canada (2012) and the recent results from the Canadian Health Measures Survey ("CHMS") 2009-2011 (Health Canada 2013) provide relevant sources for biomonitoring data. Further, although Health Canada (2012) used more biomonitoring data in evaluating children less than 6 years old in its assessment than did EPA in 2008, it would be more appropriate to use only biomonitoring data, when available, than to use the exposure activity data relied upon by EPA in the 2008 RED and by Health Canada (2012)."
   
   AD Response: The Work Plan will be revised to state that the most up-to-date information available on exposure to children under 6 years old will be considered in the upcoming risk assessment provided the information complies with EPA's Rule on Protections for Subjects in Human Research Involving Pesticides.

21. Comment: "The 2008 RED estimated aggregate risks for children less than 6 years old based on estimated triclosan exposure for infants 6 to 12 months of age and children 6-11 years of age. For infants 6 to 12 months of age, Margins of Exposure (MOEs) were estimated based on a comparison of estimated triclosan exposure from behavioral activities, including nursing, mouthing of non-food items, and hand to mouth activity that would expose the infants to triclosan in household dust and inhalation of dust. These were then combined with the MOE estimates for the 6-11 year old group to estimate a Total MOE for children less than 6 years old using the following formula."
   
   
   
   
   
   This formula appears to be a harmonic sum but the approach is not documented or transparent in the 2008 RED. An easier to understand and more directly applicable value would be to sum the daily doses across the biomonitoring estimate of daily exposure (EDD1) and the other direct exposure estimates (EDD2 [...] EDDn) and create one MOE using the following formula."
   
   
   
   
   
   AD Response: The agency's approach of aggregating the Margins of Exposure (MOE) is described at http://www.epa.gov/opp00001/trac/science/aggregate.pdf.  The agency confirms here that the results of both methods provided in the comment above are the same.

22. Comment: "Because NHANES does not include biomonitoring of children younger than 6 years of age, Health Canada (2012) relied on biomonitoring results from multiple studies in which triclosan was measured in the urine of infants and children younger than 6 years of age. These data included biomonitoring results in Canadian infants under 1 week of age and infants 2-3 months of age (unreferenced data as provided in Health Canada 2012), a study in 42 premature infants in Boston, Massachusetts (Calafat et al. 2009) and 56 children 3-6 years of age collected in Guangzhou, China (Li et al. 2011). Since the completion of the Health Canada (2012) assessment, Health Canada has acquired biomonitoring data on triclosan in their population ages 3 to 79 years of age in the second cycle of the CHMS 2009-2011 (Health Canada 2013). This data could help to inform the gap in the NHANES data for children 3 to 6 years of age. As noted in Health Canada (2012), due to the similarity of the triclosan exposure in the Canadian population to that in the US population, it is expected that these Canadian data would be representative of the US population."
   
   AD Response:  The Work Plan will be revised to state that the most up-to-date information available on exposure to children under 6 years old will be considered in the upcoming risk assessment provided the information complies with EPA's Rule on Protections for Subjects in Human Research Involving Pesticides.

23. Comment: "EPA's review should take into account the fact that the available data for triclosan in the environment do not accurately reflect representative concentrations of triclosan in the environment. Lyndall et al. (2010) conducted a comprehensive review of available triclosan monitoring data and determined that there is substantial bias in that data. Surface water and sediment data were typically collected in areas likely to be impacted by wastewater treatment plant outfalls, one of the most significant sources of triclosan discharges to water. This bias, which was present for both the surface water and sediment monitoring data, over-estimated likely surface water concentrations of triclosan in areas not directly impacted by waste water treatment plant discharges. Relying on surface water concentrations measured inside the effluent mixing zone creates a biased dataset that does not accurately characterize aquatic exposure for typical aquatic organisms. These biases in the dataset must be accounted for to ensure a representative assessment of exposure and ecological effects. Measurements collected from inside the mixing zone should be segregated from measurements taken outside of the mixing zone for the assessment, requiring a detailed review of each data source."
   
   AD Response: The agency thanks Colgate for its comment and will consider it as it conducts the registration review of triclosan.

24. Comment: "In addition, the database for triclosan measured in environmental media, summarized in Tables 20 and 21 of the Preliminary Work Plan, is incomplete. Lyndall et al. (2010) compiled an extensive database of triclosan monitoring data, including studies not included in Table 20. EPA should conduct a comprehensive literature review to complete the monitoring database."
   
   AD Response: Thank you for submittal of this reference.  The agency will consider any relevant peer-reviewed literature in the risk assessment phase of registration review. 

25. Comment: "The surface water data presented in the Preliminary Work Plan are apparently based on measured effluent concentrations from two textile manufacturing facilities. Although in-stream triclosan concentrations are presented in the work plan and Appendix B, they are not actual measured concentrations in surface water, but rather predicted concentrations assuming an extremely conservative dilution ratio applied to effluent samples. EPA is not using measured in-stream surface water concentrations because they only sampled effluent before mixing with surface water.
   
   To avoid mixed sources and ensure the assessment reflects ecological populations and communities inhabiting surface water, a more sophisticated modeling approach is warranted (e.g., a geo-referenced, fugacity-based model such as the one used in Lyndall et al. 2010). Using a "worst case" dilution factor to simulate surface water concentrations is inappropriate for the assessment of ecological populations and communities outside the effluent mixing zone."
   
   AD Response: Thank you for submittal of this reference and modeling approach.  The agency plans on using the effluent information to characterize risk, not the predicted in-stream concentrations due to the facilities mixing zones.  The agency recognizes that different facilities will have different mixing zones.  Depending on the need, if any, during the risk assessment phase to refine risks and mitigation approaches, alternative modeling approaches will be taken into consideration.
   
26. Comment: "The wastewater treatment plant removal efficiency of triclosan is greater than the 80% efficiency cited in Appendix B of the Preliminary Work Plan. The triclosan removal efficiency ranged from 91 to 99% (mean = 97%) in activated sludge waste water treatment plants in the U.S. (Bock et al. 2010), which is substantially greater than the 80% removal efficiency mentioned in the Preliminary Work Plan."
   
   AD Response: Thank you for submittal of this reference.  The agency will consider any relevant peer-reviewed literature in the risk assessment phase of registration review.

27. Comment: "Section 4.3.1 of the Preliminary Work Plan indicates that EPA is planning to assume that 100% of the triclosan contained in plastics will leach from the plastics into the environment. As noted above, EPA should use scientifically-based and realistic exposure assumptions that are representative of actual conditions. While we agree that the assessment must be protective of human health and the environment, assuming a 100% leaching rate is extreme and unsupported."
   
   AD Response: While the agency agrees this is a conservative assumption, neither leaching data for triclosan from plastics nor any model for leaching of pesticides from various plastics has been developed and submitted to the agency.  Without such information the agency has no basis upon which to support a value below 100% for use in a risk assessment.  

28. Comment: "Table 8 of the Preliminary Work Plan summarizes the toxicological endpoints and related studies relied on in the 2008 RED and suggests that these studies will be relied upon again in this review. However, the human toxicology studies relied upon in the 2008 RED were not the most appropriate at the time for evaluating triclosan and should not be relied upon in this accelerated review."
   
   AD Response: For both the reregistration and registration review of triclosan, all of the available toxicology data for triclosan in support of the human health risk assessment is considered. The agency notes that the data cited thus far is consistent with the data used by FDA and by Health Canada in their assessment of triclosan. As data become available, they will be considered for use in the updated risk assessment for triclosan. 

29. Comment: "In particular, the study from Drake (1975) (MRID 133230), used for the development of acute and chronic dietary exposure, is not an appropriate basis to evaluate chronic toxicity from triclosan...
   This study, which was conducted prior to EPA establishing good laboratory practice ("GLP") guidelines, involved only 14 animals and had an endpoint that was equivocal as to whether it was adverse. Despite these shortcomings, this study was used as the basis for all oral effects (acute dietary, chronic dietary, and short-term intermediate-term incidental oral effects), and all effects were assessed through the same toxicity value of 0.03 mg/kg-day. Nonetheless, the Preliminary Work Plan indicates that EPA appears to plan to continue to rely on the Drake study.
   
   For example, the Preliminary Work Plan identifies the finding of intermittent diarrhea at the 30 mg/kg-day level as the NOAEL in the Drake (1975) study. However, there were no changes in hematological, blood chemistry, or morphological changes noted in the animals at any of the time periods. The only adverse effect noted was an increase in intermittent diarrhea in the two highest dose groups (100 and 300 mg/kg-day), and the severity of the effect was dose related. It should also be noted that the doses in animal studies are several times higher than levels people are exposed to in consumer products (i.e., approximately 0.01 mg/kg-day), levels that have been tested in human volunteers with no adverse effects (Rodricks et al. 2010, Cullinan and Seymour 2010, Allmyr et al. 2009). Further, the endpoint and concentration identified by EPA in the Preliminary Work Plan as the NOAEL was not viewed as adverse by the authors of Drake (1975). Specifically, Drake (1975) states the following in the abstract of the study:
   
   In the absence of intermittent diarrhea the daily administration of 100 mg/kg was the "no effect" level for the baboon. Treatment with 30 mg/kg was devoid of any effect.
   No other chronic studies conducted in animals with triclosan note gastric irritation or diarrhea in any of the other studies of baboons or in other species, which further calls into question this endpoint."
   
   AD Response: Any new data that are relevant to the assessment of acute and chronic dietary exposure for triclosan will be considered for the updated risk assessment.  The agency has not stated that it would not consider any new data in updating the endpoints selected for acute and chronic dietary risk assessments. 

30. Comment: "Other chronic studies that are only briefly described in the Preliminary Work Plan require further review if they are to be used when evaluating chronic toxicity. Unlike Drake (1975), all of these studies met EPA's GLP guidelines, were larger in size, and were chronic in duration. Thus, these studies were more representative than Drake (1975) for evaluating chronic risk, but each still has issues of concern.
   :: The 18-month study in mice cited by EPA as Norman (1996) is not suitable as a basis because, as appropriately noted by EPA, the endpoint of liver tumors and associated liver toxicity is not representative of human risks due to differences in the metabolic pathway between mice and humans.
   :: A study in rats, Yau and Green (1986), resulted in some statistically significant alterations in hematological parameters, but these did not change in a dose-related fashion and the findings were not accompanied by signs of functional impairment and thus did not appear to be adverse.
   
   AD Response:  As noted in the previous comment, any data that are relevant for assessment of acute and chronic dietary exposure to triclosan will be considered in the updated risk assessment. The studies cited in the above comment have been reviewed by the agency and will be considered in the risk assessment. 

31. Comment: "The appropriate source of data for the development of an acceptable triclosan chronic oral exposure would be the data on kidney toxicity from the chronic study in hamsters reported by Chambers (1999) [MRID44874001], which was evaluated in the 2008 RED and is included in Table 14 of Appendix A of the Preliminary Work Plan. This was a large study that was conducted consistent with GLP requirements. In the study four groups of 60 male and 60 female hamsters were dosed at 0 (control), 12.5, 75, or 250 mg/kg-day for 90 (female) or 95 weeks (males). Statistically significant changes in males and females were only observed at the highest dose tested of 250 mg/kg-day, a dose that is many times higher than representative human exposures (i.e., approximately 0.01 mg/kg-day) and levels that have been tested in human volunteers with no adverse effects (Rodricks et al. 2010, Cullinan and Seymour 2010, Allmyr et al. 2009).
   
   The Preliminary Work Plan identified a NOAEL of 75 mg/kg-day based on Chambers (1999) for these endpoints in Appendix A, Table 14. An investigation by Rodricks et al. (2010) that included a comprehensive review of the chronic data provided a benchmark dose of 47 mg/kg-day, a NOAEL equivalent, based on the kidney toxicity endpoint in Chambers (1999). Either of these doses would serve as a more representative basis for chronic toxicity than the 30 mg/kg-day NOAEL from Drake (1975) provided in Table 8 of the Preliminary Work Plan."
   
   AD Response: The above comment is noted. This study and other chronic toxicity studies were summarized in the 2008 triclosan toxicology chapter in support of the RED. The endpoints previously selected in the RED will be re-examined during the risk assessment phase of registration review to determine if any endpoints should be updated based on all available data.  
   
32. Comment: "The 2008 RED and the Preliminary Work Plan do not provide a rationale for the selection of the Drake (1975) study as basis estimating an acceptable acute exposure level to triclosan. In particular, both the Preliminary Work Plan and the 2008 RED note that acute toxicity is very low. The 2008 RED identified acute toxicity as low as level IV, and the Preliminary Work Plan at p. 73 states: "Based on submitted mammalian data triclosan is considered practically nontoxic on an acute basis (rat LD50 >5000 mg ai/kg-bw; MRID 342069-01)." EPA's approach of deriving an acute toxicity value from a chronic toxicity evaluation is not appropriate, particularly given the acknowledged low acute toxicity of triclosan."
   
   AD Response:  The Drake (1975) study was selected for assessment of acute dietary risk. The assessment of acute dietary risk differs from acute systemic toxicity assessment.  Acute toxicity studies by the oral, dermal, and inhalation route are designed to assess the dose at which lethality occurs and these data are used for pesticide labeling purposes.  Acute dietary assessment in contrast does not use lethality as the endpoint, but focuses on a single exposure that causes adverse non-lethal effects.  If clarification is needed in the updated risk assessment for triclosan to distinguish these two aspects, language will be added to clarify this. 

33. Comment: "The Preliminary Work Plan cites Burns (1996) (MRID 44389708) as the source of a NOAEL of 0.6 mg/animal for dermal sensitization. However, considerable human exposure data suggests that dermal irritation is not an issue within the relevant concentration range. Studies to evaluate dermal irritation have been conducted with human volunteers, and include exposure to triclosan alone or together with sodium lauryl sulfate ("SLS") (Colgate Palmolive Company 1972, Bendig 1990, Barkvoll and Rolla 1994). The only adverse effect noted in these studies was from a study involving 10 hand washings in a 2 hour period using a detergent solution with 2% triclosan (Bending 1990). However, based on data on SLS, the irritation was likely related to exposure to SLS rather than to triclosan. Sensitization and photo sensitization studies have also been conducted and have not found evidence of sensitization (Colgate Palmolive Company 1972, Marzulli and Maibach 1973, DeSalva et al. 1989). These studies are not mentioned as part of the discussion of toxicity data in Table 8 or in the Appendix of the Preliminary Work Plan, and should be included in any final work plan."
   
   AD Response: The Burns 1996 study was not selected to characterize dermal sensitization of triclosan. Table 13 of the Preliminary Work Plan identifies the study used to characterize dermal sensitization and dermal irritation of triclosan.  That table notes that triclosan is not a dermal sensitizer and only a mild dermal irritant, consistent with the comment.  Use of human studies by the agency must comply with EPA's Rule on Protections for Subjects in Human Research Involving Pesticides. When experimental data in animals are available that show consistent responses as that observed in humans, these data are preferred for use. Human studies would be considered significant if an adverse response is observed that is not observed from experimental studies in animals or in vitro systems, and that adverse response is important for characterizing the hazard of a pesticide chemical.  In the above noted human studies, adverse effects (dermal irritation and sensitization) are not found to result from triclosan exposure. These results are consistent with the results of animal studies on triclosan. 

34. Comment: "Approximately 800 chemicals are known or suspected to interfere with hormone receptors, hormone synthesis, or hormone conversion (WHO 2012). However, only a small fraction of these chemicals have been investigated in tests capable of identifying overt endocrine effects in intact organisms. The lack of data and consensus on methodologies and endpoints that can indicate the potential for adverse effects introduces significant uncertainty about the true extent of risks from chemicals that potentially could disrupt the endocrine system."
   
   AD Response:  This comment is not specific to triclosan. The agency has an endocrine disruptor screening program that is examining the potential for pesticide chemicals to interact with hormone systems and their potential to cause adverse effects through disruption of hormone systems. 

35. Comment: "Also contributing to this uncertainty is the critical challenge of establishing definitive links between alterations to endocrine-related endpoints and actual adverse effects. An endocrine disrupting chemical has been defined by the EPA as "an exogenous agent that interferes with the production, release, transport, metabolism, binding, action, or elimination of natural hormones in the body responsible for the maintenance and the regulation of developmental processes." (EPA 2012; http://epa.gov/endocrine/#eds). This definition incorrectly suggests that evidence of a perturbation of the endocrine system is, by itself, sufficient to conclude that endocrine "disruption" has occurred, even if the perturbation may not be enough to disrupt homeostasis and lead to adverse effects. To the contrary, adverse effects from endocrine "disruption" must be observed beyond perturbations of the endocrine system. These adverse effects are typically manifested as (1) alterations in development, (2) reproductive impairment, and/or (3) reduction in growth.
   
   If actual endocrine disruption does occur then it would be manifested as growth, development, or reproductive effects. However, these adverse effects have not been observed regarding triclosan in multiple species following subchronic (Trutter 1993, Goldsmith and Craig 1983, Schmid et al. 1994, Noel et al. 1969, Leuschner et al. 1970, Paterson 1969) or chronic (Yau and Green 1986, Auletta 1995, Chambers 1999) exposure to triclosan. Therefore, the ability of a compound to potentially cause perturbations in the endocrine system cannot be considered in isolation; rather, it must be considered in combination with evidence of adverse effects caused by such perturbations. In the case of triclosan, the weight of the evidence from the available research (listed above) in multiple species demonstrates that that endocrine disruption from consumer exposure to triclosan is not a human health concern."
   
   AD Response: A response to the agency's definition of endocrine disrupting chemicals for all pesticides is beyond the scope of the triclosan final work plan.  The agency will consider all available information on the endocrine effects of triclosan in making its determination of the potential for triclosan to cause adverse effects through interaction with endocrine systems. 
   
36. Comment: "In selecting pesticides for Tier 1 screening, EPA gave priority to those that: (1) appeared in four exposure pathways (food, drinking water, residential use, and occupational exposure), and (2) appeared in three exposure pathways where the food and occupational exposure pathways were represented. (EPA 2011b). The chemicals for the initial Tier 1 screening included chemicals that the agency, in its discretion, decided should be tested first, based upon exposure potential. Significantly, triclosan was not included in the initial 67 chemicals screened in Tier 1 (EPA 2011b).
   
   Triclosan was also not included in the second list of 134 chemicals for Tier 1 screening (EPA 2011b). For this second list of chemicals, EPA focused on a subset of chemicals that have been listed as priorities per EPA's drinking water and pesticides program. Pesticides included in this second list were those scheduled for registration review during fiscal years 2007 and 2008. Again, triclosan also was not selected for screening during the 2008 RED. Further, EPA has not yet issued test orders even for those Tier 1 chemicals identified by EPA as priority substances for screening. Accordingly, through these decisions, EPA has suggested that triclosan does not raise significant endocrine disruption concerns." 
   
   AD Response: The agency's screening of the chemicals in the EDSP should not be construed as a list of known or likely endocrine disruptors. With regards to endocrine disruption research, the agency investigated the potential for triclosan to interact with the androgen, estrogen, and thyroid hormone systems. Some of these results were presented in the 2008 toxicology chapter in support of the triclosan RED. Subsequent publications have appeared since the 2008 RED concerning endocrine effects of triclosan, and these data will be considered in the updated risk assessment for triclosan.
   

37. Comment: "The evidence for endocrine effects in mammals from triclosan is focused on studies conducted in the rat, with results indicating that triclosan can affect circulating levels of total thyroxine ("T4") at high doses of triclosan that are not representative of human exposure. While T4 changes have been seen in rats, no signs of either hypothyroidism or other effects on the thyroid were seen in several other species administered triclosan for subchronic (Trutter 1993, Goldsmith and Craig 1983, Schmid et al. 1994, Noel et al. 1969, Leuschner et al. 1970a, Leuschner et al. 1970b, Paterson 1969) and chronic durations (Yau and Green 1986, Auletta 1995, Chambers 1999), at doses comparable to those administered in the short-term rat studies (Crofton et al. 2007, Zorrilla et al. 2009, Paul et al. 2010, Stoker et al. 2010, and Rodriguez and Sanchez 2010)."
   
   AD Response: These data will be reviewed and discussed in the updated triclosan risk assessments as appropriate.
   
38. Comment: "Further, recent in vitro results indicate that the hepatic clearance of T4 in rats may be mediated by PPARα-mediated induction of CYP3A and, subsequently, UDPGT, (Paul et al. 2012, Wu et al. 2011), a mode of action not likely to be present in humans (Rodricks et al. 2010). Humans have both sensitive feedback mechanisms and extensive binding capacity that maintain thyroid hormone levels within a homeostatic range. Due to the robust nature of the human thyroid hormone system, humans are expected to be much less sensitive to these changes than rodents. This conclusion is reinforced by the results of Allmyr et al. (2009) and Cullinan et al. (2010), where no changes in thyroid hormone levels were seen in humans administered triclosan in toothpaste from 14 days up to 5 years at doses that are in the relevant range encountered from the use of consumer products. 
   
   These concerns reflect the importance of applying principles of sound science, including reaching conclusions based on the weight of the evidence (consistent with the draft guidance provided as part of the EDSP (EPA 2010), taking species differentiation and modes of action into account, and evaluating data in light of representative exposures."

   AD Response: The agency is aware of the data that suggest a mechanistic basis for the increased hepatic clearance of T4 in rats. As part of the updated risk assessment for triclosan, the relevance of the proposed mechanism of T4 clearance for humans in the context of human risk will be considered. 

39. Comment:  39 A: "In its report to the FIFRA Science Advisory Panel ("SAP") titled "Integrated Approaches to Testing and Assessment Strategy: Use of New Computational and Molecular Tools," (EPA 2011c), through which EPA introduced the IATA approach, triclosan was used in a "case study" to illustrate the use of the IATA process. While the Preliminary Work Plan does not explicitly state whether the IATA will be utilized in the current review of triclosan, there are serious flaws in the triclosan "case study" that precludes its use in this review.
   
   The "case study" for triclosan discussed precursor events involving the effect of triclosan on the thyroid hormone system in rats that form the basis for the AOP (EPA 2011c). EPA proposed that the molecular initiating event in the AOP for triclosan's effect on the circulating T4 is activation of the pregnane-X-receptor (PXR) and/or the constitutive androstane receptor ("CAR") in the liver, followed by up-regulation of hepatic phase I and phase II enzymes and hepatic transporters. The up-regulation of these enzymes and transporters results in increased catabolism of T4 with a resulting decrease in circulating T4, tissue T4, and limited evidence of a decrease in T3. This "case study" relied on the rat studies discussed above, which should not be relied upon based on the lack of human relevance of the mode of action in rats, and the use of exposure concentrations not representative of actual human exposures." 
   
   39 B: "Significantly, the FIFRA SAP also raised a number of concerns regarding EPA's IATA report. On May 24-26, 2011 the FIFRA SAP held an open meeting to address a set of scientific issues associated with EPA's IATA report. Referring to the triclosan "case study", the FIFRA SAP concluded that: [I]n the case of triclosan, the experimental data does not seem to fit the typical pattern expected from perturbations on the thyroid system, since TSH levels are unchanged despite the decrease in T4 following exposure to triclosan. While the free hormone concentrations are important to know, a more critical barometer to outcome is the state of the feedback loop that controls endogenous thyroid function (i.e. TSH/TRH levels). Because the pathology (triclosan toxicity) does not appear to map correctly on the physiology (thyroid hormone feedback loop), the pathway for the adverse outcome appears to be missing key information, and thus the Panel recommended that the AOP needs to be revised and refined. (EPA 2011d)
   
   In the SAP's detailed deliberations, the panel noted: One example on which the agency should focus is the dose-response extrapolation from in vitro to in vivo. As highlighted by the triclosan example during the agency's presentation, the in vitro cell culture systems could not test concentrations greater than 2 μM triclosan (579 ng/mL) because of observed cytotoxicity, while in the in vivo dosing studies, the pups had plasma concentrations of triclosan in the range of 34 to 138 μM (1000 to 40000 ng/mL). This disparity in exposure-response must be better understood to facilitate accurate extrapolation. Development and use of microfluidics and other dynamic in vitro culture systems will be useful for modeling and extrapolating kinetics and effects from in vitro to in vivo scenarios. (EPA 2011d). Therefore, EPA cannot rely on the flawed IATA triclosan "case study" as a framework for evaluating triclosan in this registration review because the study was based on rat studies that are not applicable to humans and for the reasons set forth by the SAP.
   
   AD Response: The agency is aware of the SAP's characterization of the adverse outcome pathway (AOP) that was presented for triclosan as a case study for the IATA report. As noted in response to an earlier comment, the agency will consider all the available information when characterizing the human relevance of triclosan's effect on the thyroid hormone system. 
   
40. Comment: "The Preliminary Work Plan erroneously states, in Appendix C, that triclosan is `highly acutely toxic to freshwater fish and invertebrates.' This description is not supported by the data or studies listed in Table 25 of Appendix C, as the cited studies do not conclude that triclosan is "highly toxic" at anything approaching environmentally relevant concentrations. Lyndall et al. (2010) evaluated community level effects based on published data for 29 species, and concluded that triclosan risks to aquatic receptors were minimal at environmentally relevant concentrations."
   
   AD Response: The agency uses the toxicity categorization scheme from Brooks et al. (1973) to categorize pesticidal active ingredients.  For aquatic fish and invertebrates an acute LC50 or EC50 of 0.1  -  1 mg/L (or 100  -  1,000 ug/L) is categorized as highly toxic.  For formulations, the categorization requires expression in terms of the active ingredient before categorizing, which was performed in Table 25.  The categorization in Table 25 is correct.  The submitter appears to be confusing categorization of inherent toxicity for comparative purposes with categorization of risk levels.  

41. Comment: "The Preliminary Work Plan also incorrectly characterizes the ecotoxicity data that was available at the time of the 2008 RED, and does not include currently available ecotoxicity data. The Preliminary Work Plan (at p. 25) states that "[d]ue to lack of available ecotoxicity data . . . [the 2008 RED] only addressed acute risk to freshwater fish and aquatic plants." However, toxicity data was available for algae, invertebrates, macrophytes, fish, birds and mammals in 2008, and that data set is more robust now. The ecotoxicity data set available as of 2010 was summarized in Lyndall et al. (2010) and Fuchsman et al. (2010), and should be included in EPA's work plan."
   
   AD Response: The commenter is correct that the paragraph referenced (p. 25) in the PWP incorrectly characterizes the ecotoxicity data available at the time of the 2008 RED.  This paragraph will be updated to indicate that, while acute effects to freshwater invertebrates and fish, birds and mammals where conducted, no acute or chronic assessment for estuarine/marine invertebrates and fish, and no chronic assessment for freshwater fish were conducted.  Thank you for submitting the references for ecotoxicity data sets.  While the agency is not adding these references to the final work plan, they will be considered during the effects analysis described in Section 4.4 conducted during the risk assessment phase of registration review.  
   
42. Comment: "In particular, a comprehensive risk assessment was conducted and published in Lyndall et al. (2010), Fuchsman et al. (2010), and Bock et al. (2010). The probabilistic community level risk assessment approach was reviewed and supported by Mackay and Barnthouse (2010). This work was not identified in the Preliminary Work Plan. The aquatic risk evaluation (Lyndall et al. 2010) compared modeled and measured surface water concentrations to the species sensitivity distribution. An HC5 was estimated based on 29 species. The results of the risk assessment indicated that triclosan posed minimal risk to aquatic communities. The terrestrial risk assessment (Fuchsman et al. 2010) evaluated triclosan as found in biosolids applied to agricultural fields. Potential triclosan exposure concentrations were orders of magnitude below effects concentrations for terrestrial receptors (except for the microbial community under a "worst case" exposure scenario). Should EPA proceed with the review of triclosan, it must take these studies into account."
   
   AD Response: Thank you for submittal of these references.  The agency will consider additional relevant effects data cited in these and risk assessment information in the risk assessment phase of registration review. 
   
43. Comment: "Lastly, the review of ecotoxicity data in Appendix C of the Preliminary Work Plan includes studies classified pursuant to EPA's guidelines as "unacceptable", "acceptable", and "supplemental," while Appendix A includes studies classified as "acceptable/guideline", "acceptable/non-guideline", "acceptable", "minimum", "FDA Review", and "unacceptable." In both appendices, it is unclear what the classifications mean and what criteria were used to evaluate the studies for classification. It appears that studies subject to the same criticisms were classified differently (e.g., lack of stability is a criticism of studies that received both "supplemental" and "unacceptable" classifications). Accordingly, consistent with its commitment to good science, EPA should be transparent in how it classifies studies and should be cautious and transparent in relying on studies that it classifies as "unacceptable.""
   
   AD Response: Study classifications are defined for ecological effects data in Section IV.A and Support Document 1 of the agency's (2004) Overview of the Ecological Risk Assessment Process in the Office of Pesticide Program.  The agency's policy regarding review of public literature can be found at 
   http://www.epa.gov/pesticides/science/literature-studies.html
   
   Study classifications for toxicology studies in support of human health are summarized here: 

   ACCEPTABLE/GUIDELINE: This category includes scientifically acceptable studies that satisfy the intent of a guideline as described in §81 through §86 of Subdivision F of the Pesticide Assessment Guidelines.

   ACCEPTABLE/NONGUIDELINE: This category includes scientifically acceptable "NONGUIDELINE" (/NG) studies intended to address specific issues or other aspects of toxicology that may be part of a pesticide's overall assessment.

   UNACCEPTABLE: This category includes scientifically invalid studies or studies with deficiencies which may or may not be upgradable. 

   For each study submitted to the agency, a data evaluation record which documents a reviewer's evaluation and study classification is created. 
   
44. Comment: "All available physical-chemical properties values should be evaluated to determine the most appropriate set of values for the risk characterization. We are aware of multiple measurements for solubility in water, vapor pressure, pKa, and Henry's Law constant that are not included (see Lyndall et al. 2010). EPA should perform an updated and comprehensive literature search to identify all relevant values. Beyer et al. (2002) provide a method for deriving internally consistent values for physicochemical properties that consider all of the available data, weighted by quality. This method ensures that the physicochemical parameters are thermodynamically consistent with each other."
   
   AD Response: Thank you for these references.  The agency will consider the relevance of these studies toward characterizing fate and exposure in the risk assessment phase of registration review.
   
45. Comment: "Additional QSAR modeling may not be necessary for triclosan because it has been addressed previously in Lyndall et al. (2010), which provided a comparison of degradation rates that were measured versus those that were estimated using QSARs. In general, QSAR-derived half-lives were within the range of measured concentrations and, therefore, the QSAR-derived half-lives are used to populate the model in Lyndall et al. (2010)."
   
   AD Response: Thank you, the agency will consider the information provided when considering final values to use in the risk assessment phase of registration review.
   
   
                 Submitter: ENVIRON International Corporation
   
   
46. Comment: "The figure titled "Conceptual Model for Environmental Exposure from Treatment of Textiles with Triclosan" (Figure 1) does not adequately delineate the relationships between effects resulting from exposures to each receptor class:
   :: The WWTP microorganism pathway is incomplete: This pathway does not indicate how changes in WWTP microorganism respiration will result in increased ecological risks to the target receptor groups outlined in Table 10 of the Work Plan. This pathway should be further delineated to indicate where risks to target organisms are introduced or the pathway should be eliminated.
   :: PCE is not defined. The referenced term "PCE" in the Food Chain and Habitat Integrity components of Figure 1 is not defined in the document. In addition, specific PCEs affected by Triclosan should be delineated."
   
   AD Response: The agency disagrees that the conceptual model does not adequately delineate the source, transport pathways, non-target receptors, and attribute changes for the triclosan textile/fabric use site.  The microbes in the WWTP are non-target receptors of concern.  The transport of triclosan (and its major degradates) from the use site to a WWTP with subsequent exposure of this non-target receptor is represented correctly in the diagram.  The conceptual model also correctly represents transport of triclosan (and its major degradates) to a WWTP with subsequent transport to surface water resulting in exposure of non-target aquatic organisms. Each receptor group has associated attribute changes for which the agency has measurement endpoints to address.  The agency agrees that the term "PCE" is not defined in the work plan, this information will be added.
   
47. Comment: "ENVIRON International Corporation is incorrectly referred to as Environmental International Corporation. Please correct the reference located in Paragraph 1, Lines 5 - 6 of Section 4.3.2."
   
   AD Response: The agency thanks ENVIRON for this correction; the final work plan has been updated.
   
48. Comment: "Revise text in row 2, column 1 of Table 11 to read: "Number of days each facility was processing textiles during the study period." Operating days do not equate to days that triclosan was used, but to the number of days the facility was engaged in activities that generate wastewater. Daily triclosan usage is dependent on each facility's production schedule.
   :: Revise text in row 3, column 1 of Table 11 to read: "Amount (lbs) of triclosan-containing formulation applied during study". The amount of triclosan used is dependent on the concentration of triclosan in the formulation for each dye-bath. This information was not available for both facilities."
   
   AD Response: The work plan was corrected based on this comment.
   
49. Comment: "Correct footnote 1 of Table 12: Correct footnote to read `Five consecutive, 24-hour composite effluent samples collected from each facility's WWTP effluent channel.'
   :: Add superscript `4' to the `In-Stream' results for Facility 2. As currently written, footnote 4 to Table 12 is not used in the table.
   :: Add footnote explaining non-detect values. Values in parentheses represent Method Detection Limits (MDLs) for the samples."
   
   AD Response: The work plan was corrected based on this comment.
   
50. Comment: "Maximum IWCs of 6.1 ng/L and 43.2 ng/L are incorrectly attributed to methyl-triclosan. Revise last three sentences in the third paragraph to read: `The results of this study showed that average and maximum in-stream wastewater concentrations (IWC) for triclosan were 3.2 ng/L and 6.1 ng/L for Facility 1, and 33.1 ng/L and 43.2 ng/L for Facility 2, respectively. Methyl-triclosan was not detected in any of the effluent samples. The study was found to be acceptable.'"
   
   AD Response: The work plan was corrected based on this comment.
   
51. Comment: "ENVIRON agrees with EPA's statement that the textile effluent monitoring study allows the impacts from EPA and FDA uses of triclosan to be separated. The WWTPs at both of the studied facilities did not receive sanitary flows, which would have had the potential to contain triclosan from FDA-regulated uses such as triclosan-containing hand soap and other personal care products.
   :: Facility 1 sampling scheme not described. In the third paragraph, the sampling for Facility 2 is given as 5 consecutive, 24 hour effluent samples, which was the same sampling configuration used for Facility 1. Both facilities should be mentioned in this paragraph.
   :: Incorrect reference to Table 22. The last paragraph states that average and maximum effluent concentrations are in Table 22. The reference should be changed to refer to Table 23."
   
   AD Response: The work plan was corrected based on this comment.
   
52. Comment: 
   "::Revise text in row 2, column 1 of Table 22 to read: "Number of days each facility was processing textiles during the study period." Operating days do not equate to days that triclosan was used, but to the number of days the facility was engaged in activities that generate wastewater. Daily triclosan usage is dependent on each facility's production schedule.
   :: The information in columns 3 and 4 of rows 5, 7, and 10 of Table 22 should be given their own rows as unique applications/parameters/characteristics, as this information pertains only to the Facility 2 layout. The current form of Table 22 is confusing, as the comments in these rows refer only to Facility 2 and are not consistent with the text in column 1.
   :: Consolidate clarifier volume information for Facility 2 into row 7, column 3 of Table 22. This location is consistent with the location of Facility 1 clarifier volumes.
   :: Remove reference to 3.8 MG in row 6, column 3 of Table 22. Column 1 indicates this row should contain concentrations, not volumes. No concentration information was available for the Facility 2 aeration lagoons.
   :: Facility 2 aeration lagoon volume should be in the same row as the volume for Facility 1 aeration lagoons of Table 22. The current location of this information (i.e., 3.8 MG) is in the row pertaining to aeration lagoon MLSS, which is inconsistent with the associated column text.
   :: Unused superscript `a' in row 6, column 2 of Table 22. There is no note associated with this superscript.
   :: Table 23 is missing the average and maximum effluent triclosan concentrations for both facilities. This data should be consistent with the information presented in Table 12."
   
   AD Response: The work plan was corrected based on this comment.
   
53. Comment: "Verify that the 96-h LC50 value for Mysid is consistent with the assumptions and data in Appendix D. See comments regarding page 113 of 116 and revise page 85 Mysid 96-h LC50 value accordingly."
   
   AD Response: The commenter is correct and these changes have been made in the work plan.  Additionally, the Web-ICE documentation for the fathead minnow to bluegill sunfish was found to be missing and was added.
   
54. Comment: "There appears to be an inconsistency between the Daphnid acute toxicity value used in the Web-ICE v3.1 ecotoxicity analysis for Mysid and the EC50 value for Daphnid provided on page 107. A value of 260 ppb was used as the input to Web-ICE while 390 ppb was given as the EC50 value on page 107."
   
   AD Response: The commenter is correct and these changes have been made in the work plan.  Additionally, the Web-ICE documentation for the fathead minnow to bluegill sunfish was found to be missing and was added.
   
                              Submitter: Vivimed
   
   
55. Comment: "The aggregate exposure issue and attendant risk, beginning on page 24, should not only consider the combined EPA and FDA scenario but also an EPA-use only scenario. This would clarify inherent exposure and risk from EPA registered uses if future circumstances necessitate this separation. Recent data from textile manufacturing, not previously available, could assist in this endeavor as could the poundage differentiation."
   
   AD Response: The NHANES database for triclosan exposure is representative of exposures to triclosan from all sources. It is not possible to separate those exposures occurring only from EPA-registered uses from those occurring through FDA-registered uses. As the NHANES database is considered a reliable source of exposure data, this is the dataset that will be used to characterize aggregate exposure to triclosan 
   
56. Comment: "Your assumption that triclosan does not have a common mechanism of toxicity with other chemicals (3.4.2) appears valid. However, since there are many references to the use of structure activity relationships (SAR), amongst others, in the literature dealing with estrogen, thyroid and dioxin similarities to triclosan, specific comments related to this would be appropriate. Your comments about the toxicologic non-relevance of the triclosan-associated dioxins helps to clarify this matter as would utilization of the existing massive toxicology database to specifically answer other issues."
   
   AD Response: The agency agrees with the commenter concerning the assumption that triclosan does not share a common mechanism of toxicity with other pesticide chemicals. Structural similarity of triclosan to other chemicals such as thyroxine and estrogen have been noted in the open literature; however, this does not suggest a common mechanism for endocrine effects. 
   
57. Comment: "The issue of environmental risk assessment (4 on page 25), given the selective algal toxicity under varied laboratory conditions, requires clarification. Algae are important for photosynthesis and are a basic aquatic food source. However, given the widespread detection of triclosan in the environment there does not appear to be any actual instances of species effects or environmental damage. These real world circumstances should be considered as part of any environmental risk assessment. The use of conditional phrases (might, could, may, etc) by interested parties without substantiation of an actual effect, while promoting political agendas, does not achieve the transparency that the agency is required to fulfill."
   
   AD Response: The agency acknowledges that there are factors in real world circumstances that potentially mitigate risks defined under modeled conditions.  Environmental conditions and other factors which potentially mitigate risks in the environment versus modeled conditions in the risk characterization which will be performed during the risk assessment phase of registration review.
   
58. Comment: "The Endocrine Disruptor Screening Program (EDSP) (page 34) indicates that EPA will require the submission of EDSP screening assays for triclosan. This does not appear justified given the existing data base as well as the extensive literature on endocrine activity covering estrogenic, androgenic and thyroid-related effects. Included for your information on this matter is a recently completed document entitled `Triclosan Endocrine Disruption, Fact, Fiction or Wishful Thinking.'"
   
   AD Response:  The agency agrees that there are several published studies on the interaction of triclosan with endocrine systems in several mammalian species. The agency will determine whether the data that exist on triclosan's interaction with endocrine systems satisfy the requirements of the EDSP program or whether additional studies are needed. 
   

   REFERENCES
   
   Geigy. 1981. Geigy Scientific Tables, Volume 1. Units of measurement, body fluids, composition of the body, nutrition. Eigth edition. (Edited by C. Lentner). CIBA-GEIGY.
   
   Kline, 2005. Specialty Biocides North America 2004-2005, Kline and Company, Inc.
   
   Mage D.T., Allen, R.H., Kodali, A. 2007. Creatinine corrections for estimating children's and adult's pesticide intake doses in equilibrium with urinary pesticide and creatinine concentrations. J Exposure Sci Environ Epidemiol 1-9.  

   Schafer, K.S,, Reeves, M., Spitzer, S., Kegley, S. E. 2004. Chemical Trespass: Pesticides in Our Bodies and Corporate Accountability.  Pesticide Action Network North America. May 2004.