Agency Response to Arch Chemical's Phase I Comments Regarding PHMB Preliminary Risk Assessment November 22, 2005 Case 3122 PC Code 111801 Office of Pesticide Programs Antimicrobials Division U. S. Environmental Protection Agency 1200 Pennsylvania Avenue, NW Washington, DC 20460 Page 2 of 33 On July 15, 2004, the PHMB technical registrants received the preliminary risk assessment ( PRA) for poly( hexamethylenebiguanide) hydrochloride ( PHMB) from the Antimicrobials Division for Phase I of the reregistration process. On August 13, 2004, Arch Chemicals, Inc. made comments on the PHMB PRA. The Antimicrobials Division has prepared this document to respond to all the comments from Arch Chemicals.

The comments and responses to the comments are listed below:

Arch's Comments: PHMB is regulated by the EPA only under FIFRA, as all registered uses are classified as nonfood uses. We believe that the extension of dietary assessments to be inappropriate by FDA under FFDCA Section 409 when there are no food uses regulated by EPA under FFDCA Section 408. The use of dietary risk assessments and the associated standards under Section 408, as required for food uses regulated by EPA under the 1996 Food Quality Protection Act amendments to FFDCA, are an unreasonable extension of the Agency's authority under FIFRA and are an ad hoc imposition of additional requirements. We believe that the extent of the Agency's authority under FIFRA 2( bb) is limited to the type of indirect incidental oral ingestion which is pertinent to product regulated by EPA as nonfood pesticides under FIFRA.

EPA Response: Based on a review of product labels containing PHMB, four uses, 2 disinfectants, latex adhesives, and tunnel pasteurization, have been identified as having the potential to cause indirect dietary exposure due to indirect food contact. The Agency's reasoning and authority for conducting the dietary risk assessment is further explained later in this document.

Arch's Comments: 1.0 Executive summary Paragraph 1 refers to PHMB use as a " preservative for flowers". As we understand this use, the purpose of the PHMB in this case is to prevent microbial growth in the cut flower water, hence keep the water clean and odor free. To call this a preservative for flowers ( hence associated uses considered for outdoor use) is false and should be corrected.

EPA Response: " Preservative for flowers" has been changed to " preservative for cut flowers" throughout the document.

Arch's Comments: 2.1 Chemical Identification Vantocil IB is registered as a material preservative only and Vantocil P is registered as a manufacturing use product only. Also, the RED document says in multiple places, that the use of PHMB in swimming pools is as a fungicide and/ or algicide, and not that it is a sanitizer against bacteria.

EPA Response: This has been corrected to list PHMB as a sanitizer in swimming pools in the document. Page 3 of 33 Arch's Comments: 3.0 Hazard Arch's predecessor company, Avecia, responded to EPA's first and second HIARC report on PHMB via letters dated October 21, 2002 and March 18, 2004 ( copies attached). Both of these letters point out EPA's erroneous use of old, outdated and unacceptable studies in quoting acute toxicity values for PHMB. There are several acceptable or tentatively acceptable valid acute toxicity studies on PHMB that should be correctly referred to regarding PHMB's acute toxicity effects, particularly with regard to skin and eye irritation. These are outlined in the acute toxicity data table attached to this letter.

EPA Response: Document currently reflects only acceptable studies.

Arch's Comments: The rabbit developmental toxicity study summary ( MRID 42865901) refers to " increased mortality" at 40mg/ kg. In fact, only one death actually occurred at 40mg/ kg/ day, and this was most likely as a consequence of mal dosing. One other animal was sacrificed for humane reasons because of poor condition; the remaining four were killed because they aborted and, without fetuses for evaluation, no longer served a purpose on the study. The statement regarding " increased mortality" needs to be revised to include those comments or removed.

Summarizing the rat developmental toxicity study MRID 65131), comment is made to effects seen at a dose of 100mg/ kg/ day. Whilst the actual dose given was 2000ppm, this equates to 172.4mg/ kg/ day, and not 100mg/ kg/ day as quoted. In addition, extra ribs in the fetus are also mentioned. These have been shown to be transitory and associated with non specific maternal toxicity and reference to such should be made.

EPA Response: The document has further characterized the effects observed and explained that there were no increased susceptibility of offspring to the developmental or reproductive effects of PHMB.

Arch's Comments: Reference is made to a developmental toxicity study in mice ( MRID 93191029). This was considered unacceptable by the agency at early stages of re registration ( US EPA 3/ 9/ 95 Reregistration Status Report Card for PHMB), but no repeat study was required because both the rat and rabbit developmental toxicity studies were considered acceptable. Consequently, any reference to the mouse developmental study should be deleted.

EPA Response: Study is no longer in the document.

Arch's Comments: The high dose for the dog study is given as 75mg/ kg/ day. The actual dose given in the diet to the animals was 3000ppm. However, the test facility calculates the mean dose value for this 3000ppm dose to be 91mg/ kg, and not the 75mg/ kg as given. Page 4 of 33 EPA Response: Dose was corrected in document.

Arch's Comments: Comments on the carcinogenicity studies in rats and mice refer to significant trends seen in the incidence of vascular tumors. Although a significant increase in vascular tumors was seen at the high dose of 4000ppm , that dose was in exceedance of the MTD for studies of this type and, hence, is not relevant for an assessment of the likely carcinogenic risk, as confirmed by EPA in the 7/ 16/ 2003 CARC Report. Any increase in vascular tumors observed at the low and middose were well within the historical control range for the C57 mouse used in the study.

EPA Response: The Committee found that the dose was adequate not excessive.

Arch's Comments: Regarding the comments on the dermal carcinogenicity study, it should be noted that the mid dose was 6.0mg ( 2% PHMB in ethanol) and not the 20% in ethanol as indicated. Reference is also made on " increasing trends for liver angiosarcomas". Contention of this evaluation is given in more detail in comments made on the Toxicology Disciplinary Chapter. Furthermore, the CARC itself concluded that these tumors should be considered equivocal, hence we would contest that it is inappropriate to mention them in this summary.

EPA Response: This error has been corrected, and the document now shows 6.0 mg is equivalent to 2% PHMB in ethanol.

Arch's Comments: Avecia's two responses to the HIARC reports, mentioned above, thoroughly reviews the PHMB toxicology endpoint selection for PHMB risk assessment. We wish to reiterate here that the PHMB dermal absorption factor is estimated to be less than 1% ( MRID 45710806) and that it is incorrect to assume a 100% dermal absorption factor. Further discussion on the HIARC is provided below.

EPA Response: The current document uses dermal studies, and, therefore, no dermal absorption factor is necessary. This issue was also previously addressed in the response to comment document for the HIARC Report ( ISSUE 1, page 2 of 6, September 24, 2004).

Arch's Comments: Water Exposure and risk It is our understanding that PHMB is used to preserve water for cut flowers and not as part of liquid plant food. Consequently, this is an indoor and not an outdoor use, and the appropriate corrections should be made.

EPA Response: This use was always considered as such, and the document does indicate this. Page 5 of 33 Arch's Comments: Aggregate exposures and risk Please refer to comments on the dietary risk assessment. In summary, a dietary risk assessment is not required and it is, therefore, incorrect to include dietary assessment in the aggregate risk assessment.

EPA Response: Addressed below.

Arch's Comments: Incidence Report Assessments Comment is made that most of the incidences were related to irritation and/ or allergic type reactions. Whilst there is a possibility of PHMB to cause irritation type reactions, without following up on all the reported cases it is supposition to assume that the cases of allergic type reactions are a true finding, and not just further cases of irritancy. As such, we would contest that the summary review should refer to factual information, and not supposition. Relevant data show that PHMB is not a dermal sensitizer in humans ( Avecia's letter of March 18, 2004).

EPA Response: As was written in the Response to Comments document concerning the HIARC Report: The correct MRID for the guinea dermal sensitization studies is 42674201. In the study moderate dermal sensitization was observed in response to dermal application of 20.2% PHMB to female guinea pigs.

There are two PHMB human skin sensitization studies been submitted to the agency:

1. Smith, I. 1981. Human Sensitiztion Testing of Vantocil IB. Prepared by Ian Smith Consultancy, Longniddry, Edinburgh, EM32 OLH. ISC Project No. 0018. [ MRID 00127871]. Unpublished Report.

2. Kaidbey, K. 1995. An Assessment of the Contact Sensitizating Potential of Cosmocil CQ (# S2082001) by means of the maximization assay in Humans. Ivy Laboratories ( KGL, Inc.) 3401 Market Street, Suite 226 & 232. Philadelphia, PA 19104 3355. Project ID:# KS950101. [ MRID45187705]. Unpublished Report.

A total of 209 volunteers commenced the 1981 study, a total of 191 subjects completed the human repeated insult patch study, according to the study protocol, which involved induction of PHMB testing material at 2% ( v/ v) with challenge applications of six week applications at both this and lower concentrations. The conclusion of the study is that PHMB when applied under patch conditions on human volunteers at level of 2% v/ v can induce skin sensitization. In the elicitation phase, at concentration as 0.1% v/ v can elicitate the skin sensitization. The researcher discussed the irritation issue in the report. It was mentioned that low level of irritation was observed in the subjects applied at 2% showed that it is not capable of causing primary irritation reaction. The Agency considers PHMB is a dermal sensitization agent is based on the response of subjects at 0.1 0.2% v/ v at the elicitation phase of the study. Page 6 of 33 There are 27 healthy normal adult volunteers are involved in the 1995 study. None of the subjects had a medical or dermatological illness and none were sensitive to sunlight or to topical preparations and/ or cosmetics. One subject was dropped from the study during the induction phase for lack of compliance, while another withdraws voluntarily for personal reasons. The study was composed of two phases: ( 1) an induction phase, and ( 2) a challenge phase. In the induction phase, the site of application was pretreated with 0.25% aqueous sodium sulfate ( SLS) for a period of 24 hours. After pretreatment, a 1.0% ( v/ v) PHMB in water was applied to the upper outer arm, volar part of forearm or the back of each subject for either 48 hours ( or 72 hours when placed over a weekend). A total of 5 induction exposure sequences ( 24 hour SLS pretreatment followed by 48 hours of test material) were applied to each subject. No adverse effects occurred in any of the subjects. Therefore, the induction phase indicates that these individuals have not been induced by the 1.0 % v/ v of PHMB solution. After a 10 day resting period, in the induction phase, the researcher continued to challenge these subjects at 1.0% and 0.2% applied to new skin on the opposite arm for 48 hours. No adverse effects or unanticipated reactions were observed in any of the panelists. It is agreed that any skin irritation is sufficient grounds to terminate treatment for exposed individuals. However, in the study, none of the subjects had any signs of irritation in the induction phase of the study. Therefore, given the limited number of individuals involved in the study and inadequate dosing in the induction phase, the Agency considers the Kaidbey ( 1995) study inadequate to assess the dermal sensitization potential of PHMB.

Arch's Comments: 3.1 Hazard Profile Acute toxicity Please refer to the above comments on the relevant acute toxicity studies for PHMB. Further, the Agency has determined that none of the 20% PHMB products is Toxicity Category I, as evidenced by the label wording on registered products.

EPA Response: Table 3 has been updated to reflect the correct Toxicity Categories.

Arch's Comments: Developmental Toxicity The dose level for the rats are given as 50 and 100mg/ kg, whereas the actual calculated equivalent doses for the 1000 or 2000ppm administered should be 86.2 or 172.4mg/ kg/ day. In addition, this refers to the PHMB a. i. itself, and not the 20% a. i. as indicated in the text. The appropriate corrections should be made.

EPA Response: Doses have been corrected in the document.

Arch's Comments: Reiterating earlier comments made on the rabbit developmental study   reference is made to " increased mortality" at 40mg/ kg. In fact, only one death actually occurred at 40mg/ kg/ day, and this was most likely as a consequence of mal dosing. One other animal was sacrificed for Page 7 of 33 humane reasons because of poor condition; the remaining four were killed because they aborted and, without fetuses for evaluation, no longer served a purpose on the study. The statements need to be corrected or removed.

EPA Response: Although the relationship of the effect to test article has been called into question, there was an increased fetal and litter incidence of unossified and/ or fused sternebrae in offspring. There is sufficient uncertainty with regard to what caused this effect for the Agency to stay with the 20 mg/ kg/ day value.

Arch's Comments: Reference is made to a developmental toxicity study in mice ( MRID 93191029). This was considered unacceptable by the agency at early stages of re registration, but no repeat study was required because both the rat and rabbit developmental toxicity studies were considered acceptable. Consequently, it would be correct to delete all reference to this study.

EPA Response: Study was removed from the document.

Arch's Comments: Reproductive Toxicity Note that the dose level of 2000ppm refers to the PHMB a. i. itself, and not the 20.2% technical as is inferred.

EPA Response: Dose levels were corrected and are currently stated as mg active ingredient/ kg/ day.

Arch's Comments: Carcinogenicity Minor spelling error ( paragraph 2, line 2) suggest " sited" should read " sites"

EPA Response: Current document reflects this change.

Arch's Comments: Table 3 As commented previously, reference is made to both the acute eye and dermal irritation as being Toxicity Category I. However, as the Acute Toxicity Data Summary submitted along with this letter shows, a number of other acute skin and eye irritation studies on various grades of PHMB have been submitted to the Agency. What these show is that for PHMB 20% technical active, the skin irritation should be toxicity category III, and the eye irritation toxicity category II. As such, we would ask that these references be amended in the document. The Agency previously determined that the cited studies for eye irritation and dermal irritation were unacceptable and required that new studies be conducted. ( See EPA, 6/ 15/ 1978, Toxicity Branch review of all tox studies submitted under 10182 EUP 11). The studies accepted by EPA are MRID 125846 for eye irritation and 71357 for dermal irritation. Based on EPA review during FIFRA 88 Page 8 of 33 reregistration, the citation for acute dermal toxicity was rejected; the correct study citation is MRID 30330.

EPA Response: Table 3 has been updated to accurately reflect the appropriate studies.

Arch's Comments: Table 4 870.3250 90 day dermal toxicity: the table comments that the study is satisfied by the 90 day oral and dermal absorption factor. The HIARC recommend that the NOAEL of 150mg/ kg from the 80 week skin painting study be used as the dose endpoint for dermal toxicity. Correct the table to be consistent with the HIARC decision.

EPA Response: Table 4 has been updated to accurately reflect the recommendation of the HIARC.

Arch's Comments: 870.3200a prenatal development in rodents: as indicated previously, the NOAELs given are incorrect. The dose level for the rats are given as 10, 50 and 100mg/ kg, whereas the actual calculated equivalent doses for the 200, 1000 or 2000ppm administered should be 17.2, 86.2 or 172.4mg/ kg/ day. Furthermore, we dispute the Developmental NOAEL, based on the increase incidence of extra ribs in the fetus. Although there was an increased incidence of extra ribs, subsequent to the study being conducted these have been shown to be transitory in the Alpk: APfSD rat and associated with non specific maternal toxicity ( Wickramaratne, Jour Appl Tox, 8( 2), 1988). Consequently, these should not be considered as a developmental toxicity effect, but as a consequence of maternal toxicity.

EPA Response: Doses corrected in the prenatal developmental study in rodents ( 870.3700a). The Agency acknowledges the comment regarding the significance of increased incidence of extra ribs. It is understood that this effect is considered transitory and is a non specific effect. Therefore, the Developmental NOAEL will be re stated as 172.4 mg/ kg/ day and the Developmental LOAEL will be stated as > 172.4 mg/ kg/ day.

Arch's Comments: Therefore, we suggest that the maternal NOAEL is 17.2 mg/ kg/ day, and the LOAEL 86.2mg/ kg/ day, and that the developmental NOAEL is 172.4mg/ kg/ day. Please correct the table.

EPA Response: The table reflects these maternal NOAEL and LOAEL and a developmental NOAEL of 86.2 mg/ kg/ day.

Arch's Comments: 870.3800 reproduction and fertility effects: the offspring NOAEL is given as 2000mg/ kg/ day, whereas it should be 2000ppm. Page 9 of 33 EPA Response: This dose was corrected in the document.

Arch's Comments: 870.4100b chronic toxicity dogs: the mean dose values for the 300, 1500 and 3000ppm dose level as calculated by the test facility are given as 9, 46 and 91mg/ kg/ day for males and 9, 45 and 91mg/ kg/ day for females, respectively. Consequently, the LOAEL should be 91mg/ kg/ day, and the NOAEL 45 46mg/ kg/ day.

EPA Response: The LOAEL and NOAEL have been corrected in the document.

Arch's Comments: 870.4200: the summary as given is not consistent with the text as given in section 3.1 ( Hazard Profile). The table needs to be corrected.

EPA Response: Table 4 has been updated to be consistent with the text.

Arch's Comments: 870.4300 carcinogenicity in mice: the mean dose levels given for the dermal study ( 15, 150 and 750mg/ kg) refer to PHMB a. i. and not the 20% solution as indicated. In addition, regarding the comments about evidence of carcinogenicity observed, we suggest that this does not reflect the summary as given in section 3.1 ( Hazard Profile) or the conclusions of the CARC. In both cases, any effects seen were only observed at dose levels above the MTD, and in the case of the dermal study were only considered equivocal. Consequently, the summary conclusion of " evidence of carcinogenicity observed" is not appropriate and is inconsistent with the CARC conclusion.

EPA Response: The doses were corrected to accurately reflect mg of active ingredient: 55, 167, 715 mg/ kg/ day in males and 69, 217, 856 mg/ kg/ day in females. The document no longer states that " evidence of carcinogenicity observed." It now states: Classification of Carcinogenic Potential. Based on the weight of the evidence, the CARC concluded, in accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment ( July 1999), that PHMB is classified into the category " Suggestive Evidence of Carcinogenicity, but not Sufficient to Assess Human Carcinogenic Potential" by the oral and dermal routes. Quantification of human cancer risk is not required. This classification is mainly due to treatment related significant increase in vascular tumors in females via the oral route at an adequate dose.

Arch's Comments: 3.2 FQPA Considerations The provisions of FQPA apply only where there is a food use regulated by EPA under FFDCA Section 408. Since all uses of PHMB regulated by EPA are nonfood, the provisions of FQPA do Page 10 of 33 not apply. However, we agree that there is no evidence it would cause any concerns if FQPA were applicable.

EPA Response: As is discussed below, in the section on the Dietary Assessment, the Agency does not believe that all PHMB uses are nonfood uses.

Arch's Comments: 3.3 Dose response assessment Chronic dietary: the study and toxicological effects makes reference to the mouse developmental study. As mentioned previously, this study was considered unacceptable by EPA earlier in the re registration process and should be removed. In addition, as also indicated previously, the LOAEL for the rat developmental study should be 86.2mg/ kg/ day and not the 50mg/ kg/ day as quoted.

EPA Response: The study has been removed from the document.

Arch's Comments: The chronic and intermediate reference doses are based on the NOAEL for maternal toxicity from a rabbit developmental toxicity study. However, EPA guidance ( Rowlands, 1997) identifies that chronic reference doses are to be set on the basis of chronic studies, if available, and that such chronic studies can be used for the intermediate term reference dose. As such, the lowest NOAEL for a chronic study is 36mg/ kg/ day for the dietary chronic toxicity study in rats ( MRID 44059301) and should be the basis for establishing an intermediate term and chronic oral reference dose for PHMB.

EPA Response: This comment was addressed in the HIARC response to comment document of September 24, 2004 ( ISSUE 2).

Arch's Comments: Dermal exposure: The relative dermal absorption rate is given as 100%. As submitted in MRID 45710806, we believe this is not correct and suggest that a factor of less than 1% is still highly conservative for risk assessment purposes. The reasons behind this ( as outlined in MRID 45710806) are given below:

PHMB is a polymeric material, with an average molecular weight of approximately 2650 ( by size exclusion chromatography), based on an average of 10 13 monomer units but containing up to 40 monomers. Polymers such as this are not readily absorbed through the skin or via the gastrointestinal system, due to a combination of high molecular weight and poor solubility. Nor do such polymers readily break down into easily absorbable fractions.

EPA Response: The current document uses dermal studies, and, therefore, no dermal absorption factor is necessary. Page 11 of 33 Arch's Comments: In studies designed to evaluate the absorption, distribution, metabolism and excretion of radiolabeled PHMB following oral administration in rodents ( MRID 77926, 86363, 43567001, 43599901), it has been determined that there is very little absorption of PHMB, with more than 93% excreted in the faeces. Of the limited amount not directly excreted, there is very little actually absorbed ( 2 to 3%). What is absorbed tends to be the lower molecular weight fractions ( i. e., approximately MW 1230), although absorption of those fractions still is extremely low. The poor absorption from the digestive system following oral administration is not unexpected for a polymeric material such as PHMB.

Studies of the in vitro dermal absorption of PHMB clearly confirm that little to no PHMB is absorbed following dermal exposure, which is not unexpected for a material such as PHMB. There are 3 separate studies ( MRID 44046301, 44119301, and 44596001), each of which followed appropriate, scientifically recognized and valid procedures that are consistent with current guidance ( OECD 1996 and 2000, EPA 1999 and EPA 1992). These studies document that absorption of radio labeled PHMB through human epidermis is essentially nil. In a comparative in vitro study using rat and human epidermis, absorption by rat skin was much higher than by human skin ( MRID 44046301). While a percent absorption cannot be calculated on the basis of the information contained within MRID 44046301, the data from that study support essentially no absorption across human epidermis ( not detectable after 70 hr, with level of detection of 0.1 µ g/ cm2). Low but detectable levels were found in this study using rat skin. Those experimental results are consistent with data reported in the literature ( EPA 1992) that rat skin is 3 to 5X more permeable than is human skin. MRID 44119301 identified that there was greater relative absorption across human epidermis at lower initial dose levels over the 96 hr study. The highest percent absorption reported in that study was 0.15 %. MRID 44596001, which reported on absorption across human epidermis at a higher temperature ( 40 ° C) over a 24 hr period, showed that 0.007% of the applied dose was absorbed. Both the measured percentages in the two studies, along with the lack of any detectable levels in the third, support that dermal absorption of PHMB by human skin is well below 1% of the applied dose.

EPA Response: The current document uses dermal studies, and, therefore, no dermal absorption factor is necessary.

Arch's Comments: In order to determine an appropriate dermal absorption rate for PHMB, the following whole animal toxicity studies can be considered:   21 day dermal toxicity study in rat ( MRID 43045901), systemic NOAEL greater than 200 mg/ kg bw, LOAEL greater than 200 mg/ kg ( no adverse effects reported in study). It should be noted that higher doses could not be used due to the severe skin irritant effects of PHMB.   developmental toxicity study in rat ( MRID 65131, 42992101), maternal NOAEL 10 mg/ kg bw/ day, LOAEL 50 mg/ kg bw/ day ( decreased body weight, food consumption) Page 12 of 33 The ratio of the oral LOAEL to the dermal LOAEL ( 50/> 200) identifies that a factor of 25% or less could be considered as a dermal absorption factor for PHMB. Due to the high skin irritancy associated with PHMB, higher dermal application rates could not be assessed, and the 25% factor greatly overestimates dermal absorption. In this case, it may be more appropriate to use the NOAELs from the two studies, resulting in a factor of 5% or less, since no NOAEL was determined in the dermal toxicity study. Taking into account the results of the in vitro studies and the relation between rat and human skin permeability, a factor of less than 1% dermal absorption for humans is highly conservative for risk assessment purposes. This is consistent with the in vitro results and with the anticipated lack of absorption based on the polymeric character of the compound.

EPA Response: The current document uses dermal studies, and, therefore, no dermal absorption factor is necessary.

Arch's Comments: 4.1 Summary of Registered Uses As mentioned in comments on section 1.0, Para 1 refers to PHMB use as a " preservative for flowers". As we understand it, the purpose of the PHMB is to prevent microbial growth in the cut flower water, hence keeping the water clean and odor free. To call this a preservative for flowers ( hence associated uses considered for outdoor use) is not correct and needs to be corrected. The use is limited to wholesalers/ bouquet makers and florists. Further, the extensive material preservative uses of PHMB should be added. Table 5: the listed plant food use is incorrect. First of all, the use is not plant food. The registered product contains no nutrients. Also, the use instructions do not identify any homeowner uses.

EPA Response: " Preservative for flowers" was changed to " preservative for cut flowers" throughout document. Any reference to plant food was removed.

Arch's Comments: Table 5:  under " material preservatives"   it is incorrect to list the disinfectant uses under this category. Those uses should appear under " Residential and Public Access Premises".

EPA Response: This has been corrected in the document.

Arch's Comments: 4.2 Dietary Exposure/ Risk Pathway This entire section needs to be significantly revised, based on the comments specifically associated with the Dietary Risk Assessment document, which appear elsewhere in this response. It should be noted that tunnel pasteurization is associated almost exclusively with treatment of beer containers. Page 13 of 33 EPA Response: The Agency has determined that a dietary assessment is necessary when the active ingredient comes into contact with a surface that also comes into contact with food. Such indirect foodcontact surfaces do trigger a dietary assessment. The tunnel pasteurization was further explained in the document: " Because the bottles or cans are already sealed, the possibility of infiltration of this product from tunnel pasteurization water into the food appears to be minimal."

Arch's Comments: 4.3 Water Exposure/ Risk Pathway The reference to " liquid plant food" needs to be corrected; there is no registered product containing plant nutrients, and all uses are indoors by commercial cut flower handlers to help preserve previously cut flowers.

EPA Response: Any reference to liquid plant food has been removed.

Arch's Comments: 5.0 Aggregate risk assessment and risk characterization This section needs to be extensively revised, based on the corrections needed in the supporting sections and documents.

EPA Response: The current aggregate risk assessment accurately reflects the dietary intake as well as other scenarios that the Agency deemed reasonable to co occur.

Arch's Comments: General comments on Exposure Arch is participating in the American Chemistry Council Antimicrobial Exposure Assessment Task Force II. EPA has indicated on many occasions that further considerations on exposure data requirements and assessment will be held in abeyance until the task force study is completed. There is no mention of exposure assessment task force participation in any of the draft PHMB RED documents and we believe EPA is incorrect in not mentioning participation in the task force data development program.

EPA Response: While the data being generated by the ACC Task Force is likely to fulfill some of the exposure data requirements that will be issued in the RED, the Agency is under no obligation to mention Task Force participation in the RED document itself. The registrant may reply to the DCI with information about its participation in the Task Force and the data that is intended to be provided through the Task Force. Page 14 of 33 Response to PHMB Dietary Risk Assessment ( RED Chapter), dated June 9, 2003 and to the draft RED Document Arch's Comments: Disinfectant Uses The Agency conducted a dietary risk assessment for PHMB for disinfectant uses. We believe that the Agency has conducted that dietary risk assessment in error and in an arbitrary and capricious manner and that it should be eliminated from further consideration, for the reasons discussed below.

Even when FDA regulated food contact sanitizers under FFDCA Section 409, EPA always has regulated hard surface disinfectant uses, such as those registered for PHMB, as nonfood uses. Even with the transfer of regulatory responsibility for the food contact sanitizers from FDA under Section 409 to EPA under Section 408, EPA has continued to regulate hard surface disinfectants as non food uses.

EPA ( the Agency) has not, at any time, published any changes to its regulations or policies to reclassify such uses as food use, with any associated requirements for submission of data to support food use applications. The Agency has not previously, nor does it now, require the establishment of tolerances or exemptions from tolerance for registration of disinfectants. EPA confirms that the disinfectant uses are not food uses, by its statements in the Dietary Risk Assessment chapter, under Section II: " these uses do not fall under the guidelines associated with residue chemistry . There are no outstanding residue chemistry issues pertaining to this product." Therefore, the use of a dietary risk assessment model for a nonfood use is inappropriate.

The basis for the determination that hard surface disinfectants, which require a potable water rinse on any potential food contact surface, are not food contact uses can be found in " Sanitizing Solutions: Chemistry Guidelines for Food Additive Petitions" ( US FDA, CFSAN, OPA, Version 1.1, January 1993, hereafter referred to as FDA Sanitizing Guidelines). In that document, FDA clearly distinguishes food contact sanitizers, which may result in their becoming components of food, and disinfectants, which do not:

" The use of a solution as a sanitizer requires that application to a food contact surface be followed by adequate drainage prior to contact of the surface with food ( 21 CFR 178.1010 ( a)). A potable water rinse of the treated surface prior to food contact negates the intended effect of the solution as a sanitizer. Thus, a product intended for treating of a food contact surface and which is to be rinsed from the surface prior to food contact is not considered a sanitizer. Therefore, it is unnecessary to submit a petition for a regulation under 21 CFR 178.1010 for disinfectants or cleaning solutions that are to be rinsed from food contact surfaces" ( emphasis added)

FDA clearly made a determination that disinfectants and cleaning solutions are not expected to become components of food. Equally, EPA has agreed and regulated disinfectants in a manner appropriate to the decision that such products are not components of food. Had that position changed, EPA would have been required to establish tolerances or exemptions from tolerance for Page 15 of 33 those uses following the 1996 amendments to FFDCA that transferred the jurisdiction for regulation of hard surface sanitizers and disinfectants used in contact with food from FDA to EPA. It is noted that EPA has adopted the FDA Sanitizing Guidelines for regulation of food contact sanitizers which now are within EPA's authority for regulation, as evidenced by its multiple regulatory tolerance and registration decisions on these types of products since the regulatory responsibility was moved to EPA. See 40 CFR § 180.940.

FDA further discusses their approach to the determination of potential dietary intake of sanitizers. Their approach and development of a conservative " worst case" assumption were based on having reviewed extensive amounts of data over many years, and determining that in most cases, there would be no need for petitioners to develop specific residue data. In fact, the vast majority of actual data showed residues were in the range of microgram or nanogram per cm2 of treated area. Specifically,

" A review of the Agency's accumulation of experimental residue data has led to the conclusion that a " worst case" assumption for residual sanitizer solution of one milligram per square centimeter of treated surface ( 1 mg/ cm ² ) is a reasonably conservative estimate that reflects the body of data. Therefore, the petitioner may elect for the Agency to use this value for the exposure calculation or may provide its own experimental data having determined that the assumption of 1 mg residue/ cm ² is excessively high as an approximation for its formulation. In the absence of residue information, however, the Agency will perform an exposure estimate assuming this " worst case" value."

FDA then outlines how the estimated dietary intake can be calculated, in order to make a safety determination for that estimated dietary intake:

" The safety requirements depend on the chemical constituents of the sanitizer formulation and on the extent to which these constituents or their reaction products from food contact may reasonably be expected to become a part of food. The Agency will determine the toxicological studies needed to provide a reasonable assurance of no harm to the public from use of the sanitizer after establishing the probable daily intake of sanitizer residue."

" To estimate probable daily intakes three types of information are usually required: ( 1) sanitizer residues discussed above, ( 2) the mass and/ or volume of food contacting a unit area of treated surface, and ( 3) an estimate of an individual's daily intake of foods assumed to have contacted the sanitized surfaces. The Agency's calculations are intended to reflect a reasonable, yet conservative, " worst case" situation."

" The broadest coverage includes use of the sanitizer in institutional or public eating facilities. In this case, the Agency's worst case estimate assumes that all food consumed by an individual in a single day has contacted 4000 cm ² of sanitized non porous foodcontact surfaces. This contact area represents the summation of the surface area of silverware, china, and glass used by a person who regularly eats three meals per day in an institutional or public facility." Page 16 of 33 It is critical to note that FDA guidelines to determine intake are based on a contact area which is defined as " the summation of the surface area of silverware, china, and glass used by a person who regularly eats three meals per day in an institutional or public facility" ( emphasis added).

The label for the EPA registered disinfectant containing PHMB which could be used by consumers in a home environment specifically prohibits the use of the disinfectant on glasses, dishes, and utensils ( EPA Reg. No. 71661 1; Surfacine All Purpose Cleaner). Further, the use directions on the label specifically require that all surfaces must be wiped dry of any remaining solution after the specified contact time, with a potable water rinse required after that action on all surfaces that food might contact.

The other EPA registered disinfectant ( EPA Reg. No. 50096 1) clearly is not intended for use in the home or food contact uses, since its claims specifically identify it as a " hospital type" bactericide. The registered uses of EPA Reg. No. 50091 1 ( Wipex) do not suggest it would ever be sold to consumers or in a residential environment in kitchens, and we believe it is an unreasonable interpretation of the label to suggest otherwise. The Agency may wish to consider requiring that registrant to include language to better define the permissible use areas.

There is no rational, valid regulatory or scientific basis for the Agency to 1) modify on an ad hoc basis the FDA Sanitizing Guidelines to " fit" a home use of a disinfectant on a kitchen countertop, 2) adopt the FDA Sanitizing Guidelines for uses/ products which clearly and specifically were excluded from consideration by FDA, 3) attempt to adapt a regulatory scheme intended for evaluation of the safety residues of sanitizers on silverware, china and glass in institutional settings to use of entirely different types of products on countertops in home kitchens, and/ or 4) attempt to regulate the disinfectant on the basis of such an arbitrary and capricious approach.

In home use of a product such as Surfacine, any contact of edible items will be no more than, at worst, incidental and intermittent, with little likelihood any transfer of PHMB. It is more properly characterized as incidental oral ingestion from a post application exposure. We believe that the Agency's assessment of the incidental oral ingestion from post application residential exposure resulting from hand to mouth transfer from treated surfaces ( floors) is more than inclusive of any potential momentary exposure of edible items on countertops, since that assessment assumes no rinsing of residues and would qualify as a worst case for any incidental oral ingestion regardless of the surface. As such, the Agency should completely remove the erroneous dietary risk assessment from further consideration in both the Dietary Risk Assessment chapter and throughout the RED document.

EPA Response: General Background Before 1996, residues of products used to clean food contact surfaces were considered indirect food additives, and dietary exposure to such residues were therefore regulated by FDA under section 409 of the Federal Food, Drug, and Cosmetic Act ( FFDCA), rather than by EPA under FFDCA section 408. In order to market such products with pesticidal claims, a producer would have to obtain from FDA an FFDCA section 409 indirect food additive regulation/ clearance and Page 17 of 33 apply to EPA for registration under the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA). Based on proof of efficacy and taking into consideration the FDA food additive regulation/ clearance, EPA would register the product under FIFRA. EPA would not conduct a separate dietary risk assessment, but would instead consider FDA's risk determinations in approving a section 409 clearance in the FIFRA risk/ benefit evaluation.

At first, the only antimicrobial pesticides registered for use on food contact surfaces were sanitizers. Registrants wanted to market more potent antimicrobial products with higher application rates, so in the mid 1980s, EPA recognized a new class of antimicrobials, the " hardsurface disinfectants". Where such products were labeled for use on food contact surfaces, EPA considered them food use products. However, if a disinfectant required a potable water rinse after use, no section 409 indirect food additive regulation or clearance was required. Data were neither submitted nor required in support of the presumption that there were no residues after the potable water rinse. Based on FDA's lack of a requirement for section 409 clearances and proof of efficacy, EPA registered the hard surface disinfectants. 1 EPA continued to rely on FDA's evaluations of dietary risk under section 409 and EPA did not perform separate dietary risk assessments for these products.

In 1996, the Food Quality Protection Act amendments changed the FFDCA definition of " food additive" to exclude pesticide chemicals, making them subject to section 408 rather than section 409, and thus giving EPA sole jurisdiction over dietary residues from sanitizers and hard surface disinfectants, in addition to its existing FIFRA registration authority. As a result, FDA ceased performing dietary risk assessments for these products. The FQPA amendments to section 408 also included several new provisions that, for the first time, expressly required EPA to address certain factors in its dietary risk assessments. Moreover, FQPA amendments to FIFRA section 2( bb) require that all dietary exposures from the use of a pesticide be assessed and found to meet these new section 408 standards. 2 1See EPA's efficacy data requirements for sanitizing rinses, DIS/ TSS 4 ( Jan. 30, 1979): " Sanitizers applied to food contact surfaces are defined as incidental food additives under the Federal Food, Drug, and Cosmetic Act, as amended ( 21 U. S. C. 201 et seq.), and require establishment of a food additive tolerance. Recommendation of a potable water rinse after treatment does not preclude this requirement." Id. at 1.

2FIFRA section 3( c)( 5) prohibits EPA from registering a pesticide that would cause unreasonable adverse effects on the environment. As amended by the FQPA, FIFRA section 2( bb)( 2) provides that the term unreasonable adverse effects on the environment includes " human dietary risk from residues that result from a use of a pesticide in or on any food inconsistent with the standard under section 408 of the Federal Food, Drug, and Cosmetic Act ..." Accordingly, EPA must conduct a dietary risk assessment for any use of a pesticide product likely to result in dietary exposure to the pesticide or its degradates, and must conclude that the dietary exposure meets the FFDCA section 408 safety standard in order to conclude that the pesticide product does not cause unreasonable adverse effects pursuant to FIFRA section 2( bb). Page 18 of 33 Transitional provisions included in the FQPA amendments ( see section 408( j) & ( k)) gave the previously issued FDA food additive regulations and clearances continuing effect, so the FQPA amendments had little initial impact on the registrants of hard surface disinfectants. However, in order for EPA to make a new section 408 safety finding, particularly as the safety standard was amended by FQPA, EPA generally needs more data than was provided to FDA in support of the section 409 clearances. Accordingly, applications for new registrations of food use products, and tolerance reassessment for existing products, today require substantially more data than would have been required before 1996.

General Countertop Use Requires a Dietary Risk Assessment EPA considers use of a pesticide product on any food contact surface to be an indirect food use. EPA regards kitchen countertops as food contact surfaces because food is often placed on kitchen countertops and such food has the potential to pick up residues from products used to clean those countertops. Accordingly, label claims for use on kitchen countertops are considered indirect food use claims if there is a reasonable likelihood of any residue in or on food, and require a section 408 tolerance or exemption from the requirement of a tolerance.

Products that are labeled for use on " countertops," without clear restrictions precluding use on food contact surfaces, may be used on kitchen countertops. Because kitchen countertops are food contact surfaces, products that may be used on kitchen countertops are regulated as indirect food use products. It is possible that a label claim might be restricted to specific countertops that would not be considered food contact surfaces; however, a label that merely permits use on " countertops" would allow use on kitchen countertops. Therefore, products that are labeled for use on " countertops" require a section 408 tolerance or exemption from the requirement of a tolerance, even if the label does not specifically recommend use on kitchen countertops.

This conclusion applies to hard surface disinfectants, as well as sanitizers. Although label instructions for hard surface disinfectant products direct users to use a potable water rinse following application of the product, there is still potential for pesticide residues to remain on the food contact surface and from there transfer to food. Except where the registrant or applicant submits data sufficient to support a determination that there is no reasonable likelihood of any residue in food, the Agency considers hard surface disinfectants registered for use on countertops to be an indirect food use. You are mistaken in your assertion that " EPA always has regulated hard surface disinfectant uses... as nonfood uses." The Agency clearly stated in the 1979 DIS/ TSS efficacy testing guidelines that a potable water rinse does not alter the fact that application of disinfectants to food contact surfaces require a dietary assessment:

" Sanitizers applied to food contact surfaces are defined as incidental food additives under the Federal Food, Drug, and Cosmetic Act, as amended ( 21 U. S. C. 201 et seq.), and require establishment of a food additive tolerance. Recommendation of a potable water rinse after treatment does not preclude this requirement." DIS/ TSS 4 ( Jan. 30, 1979).

Your argument that language from Section II of the preliminary Dietary Risk Assessment chapter of the PHMB RED supports the contention that disinfectant uses are not food uses misconstrues that chapter. The countertop use does not fall under the guidelines because the Page 19 of 33 guidelines only pertain to direct food contact, not indirect food contact uses. The sentence you quote from the preliminary Dietary Risk Assessment chapter that "[ t] here are no outstanding residue chemistry issues pertaining to this product" is followed by the explanatory statement that "[ t] he Agency has used available methods to estimate PHMB residues on food due to migration of these products." Thus, the Agency's statements in the preliminary Dietary Risk Assessment, when taken in full, clearly reflect EPA's policy of conducting dietary risk assessments for countertop use of disinfectants.

Finally, you noted in your comments that " Had that position [ that disinfectants are not expected to become components of food] changed, EPA would have been required to establish tolerances or exemptions from tolerance for those uses [ disinfectants and cleaning solutions identified in 21 C. F. R. 178.1010] following the 1996 amendments to FFDCA that transferred the jurisdiction for regulation of hard surface sanitizers and disinfectants used in contact with food from FDA to EPA." That view is substantially correct: As a consequence of the pesticide reregistration process, EPA recognized an absence of data supporting the assumption that disinfectants would not result in food residues. EPA is therefore currently in the process of establishing tolerances or exemptions from the requirement of a tolerance for those hard surface sanitizing and disinfecting solutions that present a reasonable likelihood of any residue in food. See Proposed Rule: Tolerance Exemptions for Active and Inert Ingredients for Use in Antimicrobial Formulations ( Food Contact Surface Sanitizing Solutions), 68 Fed. Reg. 37, 778 ( June 25, 2003).

For the foregoing reasons, EPA maintains its position that countertop use of hard surface disinfectants is an indirect food use for which a dietary risk assessment is required pursuant to FIFRA section 2( bb), even if the label requires a potable water rinse, unless the registrant or applicant submits data sufficient to support a determination that there is no reasonable likelihood of any residue in food. Products labeled for use only on specific countertops that would not be expected to be food contact surfaces ( e. g., bathrooms, lab benches) might not be considered food use products and might be eligible for registration without a dietary risk assessment.

Arch's Comments: Additional Comments: Section III of the RED Chapter, PHMB Dietary Assessment, should be eliminated in its entirety as non pertinent, both for the above stated reasons and because the Agency did not DEEMFCID consumption information or any other items mentioned within that section.

EPA Response: This section was removed from the document.

Arch's Comments: In determining the Estimated Daily Intake of PHMB used in Latex Adhesives, a use regulated by FDA under Section 409 of FFDCA, the Agency has made a calculation error in attempting to convert the potential dietary exposure to children. The FDA Chemistry Guidance for Industry for Food Contact Substances ( April 2002), assumes that the daily consumption is 3 kg/ person/ day, combining both liquids and solids. That is an adult consumption factor. EPA simply divided the estimated daily intake using an adult consumption factor by the average weight of adults ( males 70 kg, females 60 kg) or children ( 15 kg) to come up with an exposure in Page 20 of 33 mg/ kg/ day, but failed to appropriately take into account the different total consumption of children vs. adults, which needs to be made within the earlier calculation and not after the fact. It is noted that FDA does not separately address consumption of adults vs. children.

EPA Response: Since the risk from latex adhesives based on an adult consumption rate ( a worst case scenario) is significantly lower than that from the disinfectant use, the total dietary risk was solely based on the disinfectant use. For this reason, we do not believe it is necessary to adjust the consumption factors for children.

Arch's Comments: The Agency should include that the use of PHMB in latex adhesives is regulated by FDA under Threshold of Regulation ( 21 CFR 172.39). We do not believe that EPA should conduct a dietary risk assessment under FFDCA Section 408 for uses which are not regulated under that section.

EPA Response: Due to the fact that the latex exposure was significantly less than the disinfectant exposure, the final dietary exposure is solely based upon the disinfectant use. Page 21 of 33 PHMB: COMMENTS ON THE TOXICOLOGY DISCIPLINARY CHAPTER Toxicology Disciplinary Chapter Arch's Comments: 4.1 Acute toxicity Please refer to comments above, with respect to reference to the correct acute toxicology studies for PHMB.

EPA Response: Addressed above.

4.3 Prenatal Developmental Toxicity Arch's Comments: 870.3700a Rat The summary states that the rats ( note spelling error: " rats" not " rates") were fed 0, 200, 1000 or 2000ppm, and equates this to 0, 10, 50 or 100mg/ kg/ day of 20% aqueous solution of PHMB. In fact, the animals were fed diets containing 0, 200, 1000 or 2000ppm of PHMB itself, and not the 20% solution. Furthermore, the calculated equivalent dose equates to 0, 17.2, 86.2 and 172.4mg/ kg/ day, respectively. Consequently, the maternal toxicity NOAEL is 17.2mg/ kg/ day.

EPA Response: Spelling error and doses have both been corrected in the document.

Arch's Comments: In addition, although there was an increased incidence of extra ribs, subsequent to the study being conducted these have been shown to be transitory in the Alpk: APfSD rat and associated with non specific maternal toxicity ( Wickramaratne, Jour Appl Tox, 8( 2), 1988). Consequently, as these were the only toxic effects noted in the study, the developmental NOEL should be considered to be 172.4mg/ kg/ day.

EPA Response: The Agency acknowledges the comment regarding the significance of increased incidence of extra ribs. It is understood that this effect is considered transitory and is a non specific effect. Therefore, the Developmental NOAEL will be re stated as 172.4 mg/ kg/ day and the Developmental LOAEL will be stated as > 172.4 mg/ kg/ day.

Arch's Comments: 870.3700b Rabbit As before, although the test article was in the form of a 20% aqueous solution, it should be noted that the doses given are, in fact, the PHMB a. i. itself. The summary comments that " 6 rabbits died in the 40mg/ kg/ day dose group". However, this description over emphasises the toxicity of PHMB, since only one death actually occurred at 40mg/ kg/ day, and this was most likely as a consequence of mal dosing. One other animal was sacrificed for humane reasons because of poor condition; the remaining four were killed because they aborted and, without foetuses for evaluation, no longer served a purpose on the study. This should be corrected. Page 22 of 33 EPA Response: The doses have been corrected in the document. The animal deaths were better clarified in the document: " Mortality occurred in 6 rabbits at this dose. One rabbit died probably as a result of mis dosing; one rabbit was killed in extremis on day 22 due to inappetance and weight loss starting on day 11; and the remaining 4 rabbits were killed due to abortion of fetuses and thus a lack of data for analysis."

Arch's Comments: Comment is also made on the evidence of possible developmental toxicity of PHMB due to minor defects in the sternebrae. However, it should be considered unlikely that, in the absence of any other changes in foetal development, these anomalies are compound induced.

EPA Response: Although the relationship of the effect to test article has been called into question, there was an increased fetal and litter incidence of unossified and/ or fused sternebrae in offspring. There is sufficient uncertainty with regard to what caused this effect for the Agency to stay with the 20 mg/ kg/ day value.

Arch's Comments: 4.4 Reproductive Toxicity As before, although the test article was in the form of a 20% aqueous solution, it should be noted that the doses given are, in fact, the PHMB a. i. itself.

EPA Response: All doses have been verified and corrected/ adjusted where necessary.

4.5 Chronic Toxicity Arch's Comments: 870.4100a Chronic Toxicity/ Carcinogenicity Rat Regarding the comments on the carcinogenicity potential, reference is also made to the following documents submitted previously: Evaluation of the weight of evidence for the carcinogenic potential of PHMB ( MRID 45710801) Historical control data for the occurrence of haemangiosarcoma in Alpk: ApfSD Wistar rats ( MRID 45710808) Comment is made that liver hemangiosarcomas are rare in the Alpk: ApfSD Wistar rat. However, as is outlined in the above mentioned documentation, whilst hemangiosarcomas in rats tend to be uncommon and not to be present in multiple organs in the same animal, such vascular tumours should be addressed on an animal basis, rather than a specific organ. As was also presented in the documentation, evaluating all the historical control data on the Alpk: ApfSD Wistar from the test facility showed an incidence of hemangiosarcomas between 0 and 1.9% in both males and females. Consequently, the incidence of 1/ 64 as reported with PHMB is within this historical range. Furthermore, a reported incidence of 2% for hemangiosarcomas is given in the literature. Page 23 of 33 EPA Response: The CARC considered the historical control data but determined the overall increase in tumors across tissues ( 17%) at the high dose to be outside of the historical control range. This dose was considered to be adequate but not excessive.

Arch's Comments: 870.4100b Dog The dogs received dose levels of 0, 300, 1500 and 3000ppm PHMB in the diet. These are quoted as 0, 7.5, 37.5 and 75mg/ kg/ day nominal dose. However, the mean dose values for the 300, 1500 and 3000ppm dose level as calculated by the test facility are given as 9, 46 and 91mg/ kg/ day for males and 9, 45 and 91mg/ kg/ day for females, respectively. Consequently, the systemic LOAEL for male and female dogs should be 91mg/ kg/ day, and the systemic NOAEL 45 46mg/ kg/ day.

EPA Response: The doses were corrected in the document.

4.6 Carcinogenicity Arch's Comments: 870.4200b Mouse feeding Additional reference should also be made to the following documents submitted previously: Evaluation of the weight of evidence for the carcinogenic potential of PHMB ( MRID 45710801) Historical control data for occurrence of haemangiosarcoma ( angiosarcoma) in C57BL/ 10J/ CD 1 Alpk mice ( MRID 45710804) Exceedance of the maximum tolerated dose at the highest tested does of PHMB in mice. Supplementary information to MRID 44074201 ( MRID 45710805) PHMB two year oncogenicity study in mice Pathology Working Group Peer Review ( MRID 45710802)

The summary as written contains a number of factual inaccuracies. It quotes the incidence of male mice with hemangiosarcomas to be 20/ 55 for the 4000ppm dose against 6/ 55 for control, and for females 17/ 55 ( 4000ppm) against 7/ 55 control.

However, as reported following the PWG review, the actual incidence of hemangiosarcomas in male mice was 12/ 55 ( 4000ppm) against 5/ 55 ( control) and for female mice 10/ 55 ( 4000ppm) against 6/ 55 ( control).

Furthermore, the historical control incidence of hemangiosarcomas is given as being 2  15% in males and 0   9% in females. As the report on the historical control incidence shows, the actual ranges for animals with hemangiosarcomas was 1.8   18.3% ( males) and 0   10.9% ( females).

The summary also comments that haemangiosarcoma of the liver was a significant contributory factor to death of male and female mice at 4000ppm ( which EPA agreed was above the MTD for such a study based on non carcinogenic effects). As is also outlined in the above report on the historical control incidence of hemangiosarcomas, it is inappropriate to record the incidence of these particular vascular tumours by specific organ. Because of the multicentric origin of such Page 24 of 33 tumours ( and high spontaneous incidence in the C57 mouse) the most appropriate method of evaluation is by the animal and not by reference to a specific organ. Therefore, if statistical evaluation is applied to the groups excluding the 4000ppm MTD exceedance group, no statistically significant findings of vascular tumours being a cause of death are found.

Comment is also made that the 4000ppm dose, although excessive, was considered adequate. This is not correct based on the PHMB CARC report, and we would refer you to the paper on the exceedance of the MTD as outlined above. For example, body weight decreases of 47 and 32% in males and females, respectively, are clearly more than 5   10% as recommended by current guidelines. This serious effect on bodyweight gain, associated with a significant reduction in food utilisation, suggests that the 4000ppm dose group greatly exceeds the MTD and, as such, should not be used for the evaluation of any tumorigenic risk.

EPA Response: This comment is not consistent with the most recent version of the CARC Memo. Please refer to the current version.

Arch's Comments: 870.4200b Mouse dermal It should be noted that this study was considered deficient and unacceptable and invalid for an evaluation of dermal carcinogenicity by EPA at earlier stages in the re registration process. However, we do not object to the Agency's dose endpoint selection of 150mg PHMB a. i. / kg/ day for short term and immediate term dermal exposure.

EPA Response: This study is not unacceptable. It did not fulfil a guideline because it was rat specific.

Arch's Comments: The summary reports the treatment doses as being equivalent to 0, 15, 150 and 750 mg/ kg/ day of 20% PHMB solution. In fact, the animals were exposed to 0, 0.6, 6 and 30mg PHMB a. i. / mouse/ day, which equates to an overall mean during the course of the study of 0, 15, 150 and 750mg PHMB/ mouse/ day, and not the 20% solution as indicated. In addition, the summary also reports the 6.0mg treatment dose to be made up of 20% PHMB in ethanol, whereas it was actually 2% PHMB in ethanol.

EPA Response: The doses have been corrected in the document.

Arch's Comments: The summary report also goes on to discuss possible increases in tumours in mice at the top dose ( 30mg/ PHMB/ day). PHMB has been characterized as a severe dermal irritant. Because of this dermal irritation, upper limit for dosing was restrained. Although PHMB is sparingly absorbed dermally, it was obvious from the study results that irritation was severe for the mice in the high dose and this contributed to the poor condition and thin appearance noted for these animals throughout the study. It is expected that the severe dermal irritation also enhanced the absorption of PHMB from the compromised dosing sites on the animals. The enhanced absorption would Page 25 of 33 result from the destruction of the stratum corneum and permit rapid systemic absorption of PHMB. Therefore, the dermal dose would be exaggerated and the dose level not relevant for risk assessment. Mean body weight gain was also reduced in the 30.0 mg group. Overall mortality for the high dose animals was 75% compared to approximately 30% in the other groups. Collectively, these results show that the 30.0 mg dose was an MTD exceedance dose. Microscopic evaluation revealed no evidence of carcinogenicity. Potential treatment related tumors were limited to angiosarcomas in the liver of females from the 30 mg group only. The incidence of liver angiosarcomas was 1/ 50 and 1/ 50 for control males and high dose males, respectively, and 0/ 49 and 2/ 49 for control females and high dose females, respectively. Furthermore, there were also signs of hepatic inflammation within this high dose group. The generally poor condition of the mice in this group following the prolonged dermal administration to a high irritant dose of PHMB more likely led to the debilitation in their health status, making them mores susceptible to infection. Furthermore, the results at this high dose exceeding the MTD are still within the historical range for liver angiosarcomas ( 0   8%).

EPA Response: The document does acknowledge that the dose is excessive.

Arch's Comments: Consequently, as the tumour profile in the other two dose groups were normal, it cannot be concluded that PHMB " appears to be a hepatic carcinogen", as was indicated in the summary EPA Response: The document no longer claims that PHMB " appears to be a hepatic carcinogen." Page 26 of 33 PHMB: COMMENTS ON THE 2nd REPORT OF THE HIARC EPA Response: All of the comments have been addressed in the revised risk assessment and/ or Toxicology Disciplinary Chapter. However, we cannot change the HIARC Report itself without a new meeting of the Committee.

Arch's Comments: Introduction Paragraph 2 of the introduction reads as: " In this report, the NOAEL/ LOAEL values are denoted as the weight of the technical grade of the PHMB actually used in the study in mg/ kg/ day. However, for comparison purpose, the molar equivalents of pure PHMB in mg/ kg/ day is also included and is denoted in brackets "[ ]"."

However, the fundamental, yet flawed, assumption made here is that in the individual animal reports the dose levels were given as the 20% technical material test formulation. Although in all cases the test material would have been a 20% aqueous formulation, with the exception of the acute studies and in vitro and in vivo genotoxicity studies, dose levels as administered to the animals were all reported as the PHMB a. i. itself, and not as the 20% formulation.

Consequently, where in the HIARC a NOAEL is given as, for example, 20mg/ kg, it is incorrect to give the pure PHMB equivalent as [ 4]. In reality, the NOAEL for the pure PHMB a. i. would be 20mg/ kg., whereas for the 20% technical it would be 100mg/ kg. Comments to this are made throughout this document. Corrections need to be made to all such erroneous references.

Developmental Toxicity MRID 42865901 As commented earlier, although the test article was in the form of a 20% aqueous solution, it should be noted that the doses given are, in fact, the PHMB a. i. itself. The summary also comments that " 6 rabbits died in the 40mg/ kg/ day dose group". However, this description over emphasises the toxicity of PHMB, since only one death actually occurred at 40mg/ kg/ day, and this was most likely as a consequence of mal dosing. One other animal was sacrificed for humane reasons because of poor condition; the remaining four were killed because they aborted ( due to maternal toxicity) and, without foetuses for evaluation, no longer served a purpose on the study.

Comment is also made on the evidence of possible developmental toxicity of PHMB due to minor defects in the sternebrae. However, it should be considered unlikely that, in the absence of any other changes in fetal development, these anomalies are compound induced.

Report CTL/ P/ 335 The mouse developmental study was considered to be unacceptable in the earlier stages of reregistration As such, it should not be included in the HIARC assessment.

CTL/ P/ 1262 The summary states that the rats were fed 0, 200, 1000 or 2000ppm, and equates this to 0, 10, 50 or 100mg/ kg/ day of 20% aqueous solution of PHMB. In fact, the animals were fed diets Page 27 of 33 containing 0, 200, 1000 or 2000ppm of PHMB itself, and not the 20% solution. Furthermore, the calculated equivalent dose equates to 0, 17.2, 86.2 and 172.4mg/ kg/ day, respectively. Consequently, the maternal toxicity NOAEL is 17.2mg/ kg/ day and the maternal LOAEL 86.2mg/ kg/ day.

In addition, although there was an increased incidence of extra ribs, subsequent to the study being conducted these have been shown to be transitory in the Alpk: APfSD rat and associated with non specific maternal toxicity ( Wickramaratne, Jour Appl Tox, 8( 2), 1988). Consequently, as these were the only toxic effects noted in the study, the developmental NOEL should be considered to be 172.4mg/ kg/ day.

Reproductive Toxicity Study Conclusions As commented earlier, the dose levels indicated of 200, 600 or 2000ppm refer to concentrations of PHMB a. i. itself and not the 20% aqueous formulation.

HAZARD IDENTIFICATION 1. Acute reference dose Refer to comments made above on the increased mortality and incidence of skeletal abnormalities.

The dose and endpoint for establishing RfD, as based on the developmental toxicity NOAEL is 20mg/ kg/ day ( based on effects seen at 40mg/ kg/ day). The respective concentrations given of [ 4] and [ 8] for the 20mg/ kg and 40mg/ kg, respectively, is incorrect for reasons given in comments on the introduction.

3. Chronic Reference Dose Comments made earlier on MRID 42865901 are reiterated again: As commented earlier, although the test article was in the form of a 20% aqueous solution, it should be noted that the doses given are, in fact, the PHMB a. i. itself. The summary also comments that " 6 rabbits died in the 40mg/ kg/ day dose group". However, this description over emphasises the toxicity of PHMB, since only one death actually occurred at 40mg/ kg/ day, and this was most likely as a consequence of mal dosing. One other animal was sacrificed for humane reasons because of poor condition; the remaining four were killed because they aborted ( due to maternal toxicity) and, without foetuses for evaluation, no longer served a purpose on the study.

Comment is also made on the evidence of possible developmental toxicity of PHMB due to minor defects in the sternebrae. However, it should be considered unlikely that, in the absence of any other changes in fetal development, these anomalies are compound induced.

Report CTL/ P/ 335 As also commented earlier, the mouse developmental study was considered to be unacceptable at earlier stages of the re registration process. As such, it should not be included in the HIARC assessment. Page 28 of 33 CTL/ P/ 1262 Reiterating once again the earlier comments:

The summary states that the rats were fed 0, 200, 1000 or 2000ppm, and equates this to 0, 10, 50 or 100mg/ kg/ day of 20% aqueous solution of PHMB. In fact, the animals were fed diets containing 0, 200, 1000 or 2000ppm of PHMB itself, and not the 20% solution. Furthermore, the calculated equivalent dose equates to 0, 17.2, 86.2 and 172.4mg/ kg/ day, respectively. Consequently, the maternal toxicity NOAEL is 17.2mg/ kg/ day and the maternal LOAEL 86.2mg/ kg/ day..

In addition, although there was an increased incidence of extra ribs, subsequent to the study being conducted these have been shown to be transitory in the Alpk: APfSD rat and associated with non specific maternal toxicity ( Wickramaratne, Jour Appl Tox, 8( 2), 1988). Consequently, as these were the only toxic effects noted in the study, the developmental NOEL should be considered to be 172.4mg/ kg/ day.

Dose and endpoint for establishing RfD The chronic reference dose as given is based on the NOAEL for maternal toxicity from the rabbit developmental toxicity study. However, EPA guidance identifies that chronic reference doses are to be set on the basis of chronic studies, if available, and that such chronic studies can be used for the intermediate term reference dose. As such, the lowest NOAEL for a chronic study is 36mg/ kg/ day for the dietary chronic toxicity study in rats ( MRID 44059301) and should be the basis for establishing an intermediate term and chronic oral reference dose for PHMB.

5. Intermediate term incidental oral ingestion exposure We reiterate the earlier comments made about the mouse developmental toxicity study: The mouse developmental study was considered to be unacceptable at re registration. As such, it should not be included in the HIARC assessment.

Dose endpoint for risk assessment The intermediate term oral ingestion reference dose as given is based on the NOAEL for maternal toxicity from the rabbit developmental toxicity study. However, EPA guidance identifies that chronic reference doses are to be set on the basis of chronic studies, if available, and that such chronic studies can be used for the intermediate term reference dose. As such, the lowest NOAEL for a chronic study is 36mg/ kg/ day for the dietary chronic toxicity study in rats ( MRID 44059301) and should also be considered as the basis for establishing an intermediate term reference dose for PHMB.

6. Dermal Absorption Factor The relative dermal absorption rate is given as 100%. As submitted in MRID 45710806, we contest this and suggest that a factor of less than 1% is still highly conservative for risk assessment purposes. The reasons behind this ( as outlined in MRID 45710806 and in comments on the draft RED itself) are given below:

PHMB is a polymeric material, with an average molecular weight of approximately 2650 ( by size exclusion chromatography), based on an average of 10 13 monomer units but containing up Page 29 of 33 to 40 monomers. Polymers such as this are not readily absorbed through the skin or via the gastrointestinal system, due to a combination of high molecular weight and poor solubility. Nor do such polymers readily break down into easily absorbable fractions.

In studies designed to evaluate the absorption, distribution, metabolism and excretion of radiolabeled PHMB following oral administration in rodents ( MRID 77926, 86363, 43567001, 43599901), it has been determined that there is very little absorption of PHMB, with more than 93% excreted in the faeces. Of the limited amount not directly excreted, there is very little actually absorbed ( 2 to 3%). What is absorbed tends to be the lower molecular weight fractions ( i. e., approximately MW 1230), although absorption of those fractions still is extremely low. The poor absorption from the digestive system following oral administration is not unexpected for a polymeric material such as PHMB.

Studies of the in vitro dermal absorption of PHMB clearly confirm that little to no PHMB is absorbed following dermal exposure, which is not unexpected for a material such as PHMB. There are 3 separate studies ( MRID 44046301, 44119301, and 44596001), each of which followed appropriate, scientifically recognized and valid procedures that are consistent with current guidance ( OECD 1996 and 2000, EPA 1999 and EPA 1992). These studies document that absorption of radio labeled PHMB through human epidermis is essentially nil. In a comparative in vitro study using rat and human epidermis, absorption by rat skin was much higher than by human skin ( MRID 44046301). While a percent absorption cannot be calculated on the basis of the information contained within MRID 44046301, the data from that study support essentially no absorption across human epidermis ( not detectable after 70 hr, with level of detection of 0.1 µ g/ cm2). Low but detectable levels were found in this study using rat skin. Those experimental results are consistent with data reported in the literature ( EPA 1992) that rat skin is 3 to 5X more permeable than is human skin. MRID 44119301 identified that there was greater relative absorption across human epidermis at lower initial dose levels over the 96 hr study. The highest percent absorption reported in that study was 0.15 %. MRID 44596001, which reported on absorption across human epidermis at a higher temperature ( 40 ° C) over a 24 hr period, showed that 0.007% of the applied dose was absorbed. Both the measured percentages in the two studies, along with the lack of any detectable levels in the third, support that dermal absorption of PHMB by human skin is well below 1% of the applied dose.

In order to determine an appropriate dermal absorption rate for PHMB, the following whole animal toxicity studies can be considered:   21 day dermal toxicity study in rat ( MRID 43045901), systemic NOAEL greater than 200 mg/ kg bw, LOAEL greater than 200 mg/ kg ( no adverse effects reported in study). It should be noted that higher doses could not be used due to the severe skin irritant effects of PHMB.   developmental toxicity study in rat ( MRID 65131, 42992101), maternal NOAEL 10 mg/ kg bw/ day, LOAEL 50 mg/ kg bw/ day ( decreased body weight, food consumption)

The ratio of the oral LOAEL to the dermal LOAEL ( 50/> 200) identifies that a factor of 25% or less could be considered as a dermal absorption factor for PHMB. Due to the high skin irritancy associated with PHMB, higher dermal application rates could not be assessed, and the 25% Page 30 of 33 factor greatly overestimates dermal absorption. In this case, it may be more appropriate to use the NOAELs from the two studies, resulting in a factor of 5% or less, since no NOAEL was determined in the dermal toxicity study. Taking into account the results of the in vitro studies and the relation between rat and human skin permeability, a factor of less than 1% dermal absorption for humans is highly conservative for risk assessment purposes. This is consistent with the in vitro results and with the anticipated lack of absorption based on the polymeric character of the compound.

7. Dermal Exposure: Short term The summary reports the 6.0mg treatment dose to be made up of 20% PHMB in ethanol, whereas it was actually 2% PHMB in ethanol.

The report also concludes that " for 20% PHMB solution, the NOAEL = 150mg/ kg/ day". The dosing solutions were actually administered as 0.6, 6 and 30mg PHMB a. i./ mouse/ day. Consequently, as was stated in the comments to the introduction, the NOAEL ( as calculated in mg/ kg/ day) is, therefore, for the PHMB a. i. and not the 20% solution.

Therefore, the dose/ endpoint for risk assessment is also 150mg/ kg/ day of PHMB a. i.

Comment is also made as to the dermal sensitization potential for PHMB, mentioning that " PHMB is demonstrated to be a human skin sensitizer in the 1981 dermal sensitization study".

This assessment of PHMB as a potential human sensitizer is contested, and evidence supporting such was submitted in MRID 45789602. In fact, there is no evidence that PHMB is a sensitizer in either humans or animals.

In summary, PHMB has been shown to be a dermal irritant in studies with humans and animals and the degree of dermal irritation is concentration dependent. Concentrations of 2% PHMB and above have induced moderate to severe dermal irritation in both animals and humans. In addition, the dermal sensitization potential of PHMB has been evaluated in guinea pigs and humans. The overall assessment of the sensitization potential of PHMB is confounded since PHMB is a dermal irritant and, in many cases, it is difficult to separate dermal sensitization from dermal irritation responses. Overall, the results of relevant dermal sensitization studies with humans show that PHMB is not a dermal sensitizer and PHMB should not be considered a human sensitizer under conditions of use Page 31 of 33 CLASSIFICATION OF CARCINOGENIC POTENTIAL Reference should also be made to the findings and report of the CARC. This section should be revised to reflect the conclusions of the CARC.

The comments below are also made in response to the Toxicology Disciplinary Chapter:

EPA Response: All of the comments have been addressed in the revised risk assessment and/ or Toxicology Disciplinary Chapter. However, we cannot change the CARC Memo itself without a new meeting of the Committee.

Arch's Comments: Chronic Toxicity/ Carcinogenicity Rat ( MRID 44059301 and 44042801)

Regarding the comments on the carcinogenicity potential, reference is also made to the following documents submitted previously: Evaluation of the weight of evidence for the carcinogenic potential of PHMB ( MRID 45710801) Historical control data for the occurrence of haemangiosarcoma in Alpk: ApfSD Wistar rats ( MRID 45710808) Comment is made that liver hemangiosarcomas are rare in the Alpk: ApfSD Wistar rat. However, as is outlined in the above mentioned documentation, whilst hemangiosarcomas in rats tend to be uncommon and not to be present in multiple organs in the same animal, such vascular tumors should be addressed on an animal basis, rather than a specific organ. As was also presented in the documentation, evaluating all the historical control data on the Alpk: ApfSD Wistar from the test facility showed an incidence of hemangiosarcomas between 0 and 1.9% in both males and females. Consequently, the incidence of 1/ 64 as reported with PHMB is within this historical range. Furthermore, a reported incidence of 2% for hemangiosarcomas is given in the literature Carcinogenicity Study in mice ( MRID 44074201) Additional reference should also be made to the following documents submitted previously: Evaluation of the weight of evidence for the carcinogenic potential of PHMB ( MRID 45710801) Historical control data for occurrence of haemangiosarcoma ( angiosarcoma) in C57BL/ 10J/ CD 1 Alpk mice ( MRID 45710804) Exceedance of the maximum tolerated dose at the highest tested does of PHMB in mice. Supplementary information to MRID 44074201 ( MRID 45710805) PHMB two year oncogenicity study in mice Pathology Working Group Peer Review ( MRID 45710802)

The summary as written contains a number of factual inaccuracies. It quotes the incidence of male mice with hemangiosarcomas to be 20/ 55 for the 4000ppm dose against 6/ 55 for control, and for females 17/ 55 ( 4000ppm) against 7/ 55 control. Page 32 of 33 However, as reported following the PWG review, the actual incidence of hemangiosarcomas in male mice was 12/ 55 ( 4000ppm) against 5/ 55 ( control) and for female mice 10/ 55 ( 4000ppm) against 6/ 55 ( control).

Furthermore, the historical control incidence of hemangiosarcomas is given as being 2  15% in males and 0   9% in females. As the report on the historical control incidence shows, the actual ranges for animals with hemangiosarcomas was 1.8   18.3% ( males) and 0   10.9% ( females).

The summary also comments that haemangiosarcoma of the liver was a significant contributory factor to death of male and female mice at 4000ppm ( which is also contested as being above the MTD for such a study). As is also outlined in the above report on the historical control incidence of hemangiosarcomas, it is inappropriate to record the incidence of these particular vascular tumours by specific organ. Because of the multicentric origin of such tumours ( and high spontaneous incidence in the C57 mouse) the most appropriate method of evaluation is by the animal and not by reference to a specific organ. Therefore, if statistical evaluation is applied to the groups excluding the 4000ppm MTD exceedance group, no statistically significant findings of vascular tumours being a cause of death are found.

Comment is also made that the 4000ppm dose, although excessive, was considered adequate. This is not correct based on the PHMB CARC report, and we would refer you to the paper on the exceedance of the MTD as outlined above. For example, body weight decreases of 47 and 32% in males and females, respectively, are clearly more than 5   10% as recommended by current guidelines. This serious effect on bodyweight gain, associated with a significant reduction in food utilisation, suggests that the 4000ppm dose group greatly exceeds the MTD and, as such, should not be used for the evaluation of any tumorigenic risk.

Mouse dermal carcinogenicity ( MRID 00066475 and 00104796) It should be noted that this study was considered deficient and unacceptable and invalid for an evaluation of dermal carcinogenicity in the earlier stages of re registration However, we do not object to the Agency's dose endpoint selection of 150mg PHMB a. i. / kg/ day for short term and immediate term dermal exposure.

The summary reports the treatment doses as being equivalent to 0, 15, 150 and 750 mg/ kg/ day of 20% PHMB solution. In fact, the animals were exposed to 0, 0.6, 6 and 30mg PHMB a. i. / mouse/ day, which equates to an overall mean during the course of the study of 0, 15, 150 and 750mg PHMB/ mouse/ day, and not the 20% solution as indicated. In addition, the summary also reports the 6.0mg treatment dose to be made up of 20% PHMB in ethanol, whereas it was actually 2% PHMB in ethanol.

IV Hazard Characterization Minor spelling error in that " chronicrat" should read " chronic rat".

Please refer to previous comments on the PHMB acute toxicity studies for reference to the correct toxicity studies. Page 33 of 33 VII Summary of Toxicological endpoints Reference is made to the individual comments made earlier within this document, many of which have a direct impact upon the summary table. These need to be revised to be consistent with the other corrections.


[Federal Register Volume 82, Number 15 (Wednesday, January 25, 2017)]
[Notices]
[Pages 8416-8417]
[FR Doc No: 2017-01675]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Project No. 14810-000]

Chugach Electric Association, Inc.; Notice of Preliminary Permit
Application Accepted for Filing and Soliciting Comments, Motions To
Intervene, and Competing Applications

    On December 23, 2016, Chugach Electric Association, Inc. filed an
application for a preliminary permit, pursuant to section 4(f) of the
Federal Power Act (FPA), proposing to study the

feasibility of the Snow River Hydroelectric Project (Snow River Project
or project) to be located on the Snow River, near Seward in the Kenai
Peninsula Borough, Alaska. The sole purpose of a preliminary permit, if
issued, is to grant the permit holder priority to file a license
application during the permit term. A preliminary permit does not
authorize the permit holder to perform any land-disturbing activities
or otherwise enter upon lands or waters owned by others without the
owners' express permission. The project would utilize 15,957 acres of
land owned by the U.S. Forest Service.
    The project consists of two alternatives both using the following
new facilities: (1) A 700-foot-long, 300-foot-high concrete-faced
rockfill or roller compacted concrete gravity dam with a 400-foot-long
spillway built into the crest of the dam; (2) a 300-foot-long, 60-foot-
high concrete-faced rockfill or roller compacted concrete gravity
auxiliary dam on the right bank; (3) a 500-foot-long, 80-foot-high
concrete-faced rockfill or roller compacted concrete gravity auxiliary
dam on the left bank; and (4) a 5,321-acre reservoir.

Alternative 1

    (1) A 10,040-foot-long, 14 foot-diameter horseshoe intake tunnel;
(2) a 1,140-foot long, 173-inch-diameter steel penstock; (3) an 80-
foot-long, 100-foot-wide pre-engineered metal powerhouse with three
turbine units rated at 25 megawatts (MW) each for 75 MW total; (4) a
submerged tailrace discharge; (5) a 2.55-mile-long, 69-kilovolt (kV)
transmission line tying into an existing high voltage transmission line
located west of the proposed powerhouse; (6) a 1,410-foot-long access
road to the intake tunnel and dam; (7) a 6,858-foot-long access road to
the powerhouse; and (8) appurtenant facilities.

Alternative 2

    (1) A 3,310-foot-long, 14 foot-diameter horseshoe intake tunnel;
(2) a 2,650-foot long, 173-inch-diamater steel penstock; (3) the same
powerhouse, turbine, tailrace and transmission line as described above
for Alternative 1; (4) a 12,600-foot-long access road to the intake
tunnel and dam; (5) a 8,000-foot-long access road to the powerhouse;
and (6) appurtenant facilities.
    The estimated annual generation of the Snow River Project would be
341 gigawatt-hours.
    Applicant Contact: Mr. Paul Risse, Senior Vice President, Chugach
Electric Association, Inc., 5601 Electron Drive, Anchorage, AK 99518;
phone:<PHONE_NUMBER>.
    FERC Contact: Julia Kolberg, phone:<PHONE_NUMBER> or email:
<EMAIL_ADDRESS>    Deadline for filing comments, motions to intervene, competing
applications (without notices of intent), or notices of intent to file
competing applications: 60 days from the issuance of this notice.
Competing applications and notices of intent must meet the requirements
of 18 CFR 4.36.
    The Commission strongly encourages electronic filing. Please file
comments, motions to intervene, notices of intent, and competing
applications using the Commission's eFiling system at http://www.ferc.gov/docs-filing/efiling.asp. Commenters can submit brief
comments up to 6,000 characters, without prior registration, using the
eComment system at http://www.ferc.gov/docs-filing/ecomment.asp. You
must include your name and contact information at the end of your
comments. For assistance, please contact FERC Online Support at
<EMAIL_ADDRESS>(866) 208-3676 (toll free), or (202) 502-
8659 (TTY). In lieu of electronic filing, please send a paper copy to:
Secretary, Federal Energy Regulatory Commission, 888 First Street NE.,
Washington, DC 20426. The first page of any filing should include
docket number P-14810-000.
    More information about this project, including a copy of the
application, can be viewed or printed on the ``eLibrary'' link of
Commission's Web site at http://www.ferc.gov/docs-filing/elibrary.asp.
Enter the docket number (P-14810) in the docket number field to access
the document. For assistance, contact FERC Online Support.

    Dated: January 18, 2017.
 Kimberly D. Bose,
 Secretary.
[FR Doc. 2017-01675 Filed 1-24-17; 8:45 am]
 BILLING CODE 6717-01-P


[Federal Register Volume 79, Number 52 (Tuesday, March 18, 2014)]
[Notices]
[Pages 15118-15119]
[FR Doc No: 2014-05907]

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ENVIRONMENTAL PROTECTION AGENCY

[FRL-9908-28-ORD; EPA-HQ-ORD-2014-0192]

Human Studies Review Board Advisory Committee

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice. Request for Nominations to the Human Studies Review
Board (HSRB) Advisory Committee.

-----------------------------------------------------------------------

SUMMARY: The Environmental Protection Agency (EPA) invites nominations
from a diverse range of qualified candidates with expertise in
bioethics to be considered for appointment to its Human Studies Review
Board (HSRB) advisory committee. Anticipated vacancies will be filled
by September 1, 2014. Sources in addition to this Federal Register
Notice may also be utilized in the solicitation of nominees.

DATES: Submit nominations by April 11, 2014.

SUPPLEMENTARY INFORMATION:
    Background: On February 6, 2006, the Agency published a final rule
for the protection of human subjects in research (71 FR 24 6138) that
called for creating a new, independent human studies review board
(i.e., HSRB). The HSRB is a federal advisory committee operating in
accordance with the Federal Advisory Committee Act (FACA) 5 U.S.C. App.
2 Sec.  9 (Pub. L. 92-463). The HSRB provides advice, information, and
recommendations to EPA on issues related to scientific and ethical
aspects of human subjects research. The major objectives of the HSRB
are to provide advice and recommendations on: (1) Research proposals
and protocols that include human subjects; (2) reports of completed
research with human subjects; and (3) how to strengthen EPA's programs
for protection of human subjects of research. The HSRB reports to the
EPA Administrator through EPA's Science Advisor. General information
concerning the HSRB, including its charter, current membership, and
activities can be found on the EPA Web site at http://www.epa.gov/osa/hsrb/.
    HSRB members serve as special government employees or regular
government employees. Members are appointed by the EPA Administrator
for either two or three year terms with the possibility of
reappointment for additional terms, with a maximum of six years of
service. The HSRB usually meets up to four times a year and the typical
workload for HSRB members is approximately 25 to 30 hours per meeting,
including the time spent at the meeting. Responsibilities of HSRB
members include reviewing extensive background materials prior to
meetings of the Board, preparing draft responses to Agency charge
questions, attending Board meetings, participating in the discussion
and deliberations at these meetings, drafting assigned sections of
meeting reports, and helping to finalize Board reports. EPA compensates
special government employees for their time and provides reimbursement
for travel and other incidental expenses associated with official
government business. EPA values and welcomes diversity. In an effort to
obtain nominations of diverse candidates, EPA encourages nominations of
women and men of all racial and ethnic groups.
    The qualifications of nominees for membership on the HSRB will be
assessed in terms of the specific expertise sought for the HSRB.
Qualified nominees who agree to be considered further will be included
in a ``Short List''. The Short List of nominee names and biographical
sketches will be posted for 14 calendar days for public comment on the
HSRB Web site: http://www.epa.gov/osa/hsrb/index.htm. The public will
be encouraged to provide additional information about the nominees that
EPA should consider. At the completion of the comment period, EPA will
select new Board members from the Short List. Candidates not selected
for HSRB membership at this time may be considered for HSRB membership
as vacancies arise in the future or for service as consultants to the
HSRB. The Agency estimates that the names of Short List candidates will
be posted in June 2014. However, please be advised that this is an
approximate time frame and the date is subject to change. If you have
any questions concerning posting of Short List candidates on the HSRB
Web site, please consult the person listed under FOR FURTHER
INFORMATION CONTACT.
    Members of the HSRB are subject to the provisions of 5 CFR Part
2634, Executive Branch Financial Disclosure, as supplemented by the EPA
in 5 CFR Part 6401. In anticipation of this requirement, each nominee
will be asked to submit confidential financial information that fully
discloses, among other financial interests, the candidate's employment,
stocks and bonds, and where applicable, sources of research support.
The information provided is strictly confidential and will not be
disclosed to the public. Before a candidate is considered further for
service on the HSRB, EPA will evaluate each candidate to assess whether
there is any conflict of financial interest, appearance of a lack of
impartiality, or

prior involvement with matters likely to be reviewed by the Board.
    Nominations will be evaluated on the basis of several criteria,
including: The professional background, expertise and experience that
would contribute to the diversity of perspectives of the committee;
interpersonal, verbal and written communication skills and other
attributes that would contribute to the HSRB's collaborative process;
consensus building skills; absence of any financial conflicts of
interest or the appearance of a lack of impartiality, or lack of
independence, or bias; and the availability to attend meetings and
administrative sessions, participate in teleconferences, develop policy
recommendations to the Administrator, and prepare recommendations and
advice in reports.
    Nominations should include a resume or curriculum vitae providing
the nominee's educational background, qualifications, leadership
positions in national associations or professional societies, relevant
research experience and publications along with a short (one page)
biography describing how the nominee meets the above criteria and other
information that may be helpful in evaluating the nomination, as well
as the nominee's current business address, email address, and daytime
telephone number. Interested candidates may self-nominate.
    To help the Agency in evaluating the effectiveness of its outreach
efforts, nominees are requested to inform the Agency of how you learned
of this opportunity.
    Final selection of HSRB members is a discretionary function of the
Agency and will be announced on the HSRB Web site at http://www.epa.gov/osa/hsrb/index.htm as soon as selections are made.

ADDRESSES: Submit your nominations by April 11, 2014, identified by
Docket ID No. EPA-HQ-ORD-2014-0192, by any of the following methods:
    Internet: http://www.regulations.gov: Follow the online
instructions for submitting comments.
    Email<EMAIL_ADDRESS>    USPS Mail: ORD Docket, Environmental Protection Agency, Mailcode:
28221T, 1200 Pennsylvania Ave. NW., Washington, DC 20460.
    Hand or Courier Delivery: EPA Docket Center (EPA/DC), Room 3304,
EPA West Building, 1301 Constitution Avenue NW., Washington, DC 20460,
Attention Docket ID No. EPA-HQ-ORD-2014-0192. Deliveries are accepted
from 8:30 a.m. to 4:30 p.m., Monday through Friday, excluding legal
holidays. Special arrangements should be made for deliveries of boxed
information.

FOR FURTHER INFORMATION CONTACT: Jim Downing, Designated Federal
Official, Office of the Science Advisor, Mail Code 8105R, U.S.
Environmental Protection Agency, 1200 Pennsylvania Avenue NW.,
Washington, DC 20460; telephone number:<PHONE_NUMBER>, fax number:
(202) 564-2070, email<EMAIL_ADDRESS>
    Dated: March 10, 2014.
Glenn Paulson,
Science Advisor.
[FR Doc. 2014-05907 Filed 3-17-14; 8:45 am]
BILLING CODE 6560-50-P


From:
Brenna M Harden<EMAIL_ADDRESS>Sent:
Friday, January 17, 2020 12:44 PM
To:
<EMAIL_ADDRESS>Raymond, Gabrielle<EMAIL_ADDRESS>Cc:
Robert B Sanch<EMAIL_ADDRESS>Elise Ciak<EMAIL_ADDRESS>Robert H Carlin<EMAIL_ADDRESS>Ronald K Burnette<EMAIL_ADDRESS>Marion Mikel Krchmar<EMAIL_ADDRESS>David W Fanning Jr<EMAIL_ADDRESS>Subject:
EES Coke Review of Enclosure 1 Information

Dr. Jones,

Thank you for the reminder. Attached is the document with my corrections as required in the spreadsheet.

Regards,
Brenna Harden
Senior Environmental Engineer
EES Coke Battery, LLC
(o)<PHONE_NUMBER> | (m)<PHONE_NUMBER>
<EMAIL_ADDRESS>

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