UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

12/12/12 MEMORANDUM SUBJECT:

PC Code: 111801 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

Poly(hexamethylenebiguanide) hydrochloride. Revised Human Health Seeping Document for the Registration Review. DP Barcode: 0407448 Decision No.: 459594 Registration Nos. : NA Petition No(s)

.: NA Regulatory Action: Registration Review Risk Assessment Type: Single chemical Registration Review Case No.: 3122 TXR No

.: NA MRID Nos. : NA FROM:

TO:

THRU: CAS No.: 32289-58-0 40 CFR: 180.1280 

### William 

### J. Hazel, Ph.D

., Chemist,

# Scie~CoopJigator**c;;/~** Michelle Centra, Pharmacologist

### aJ:ff_~**{t!1 ~**  Timothy Dole, CIH, Industrial Hygienist,

## ~~ C'r
.. I)

# a{f Jonathan Chen , Ph.D., Incident

### Data**~** 

### CiiZ._ Risk Assessment and Science Support Branch (RASSB) Antimicrobials Division (751 OP) Rebecca von dem-Hagen, Chemical Review Manager Regulatory Management Branch II Antimicrobials Division (751 OP)

## c:::**~ ~**  

## .-- Steven Weiss, Chief

# ~ :,c_, Timothy Leighton, Senior Scientist!Team Leader Risk Assessment and Science Support Branch (RASSB) Antimicrobials Division (75 1OP)
Executive Summary Poly(iminocarbonimidoyliminocarbonimidoylimino
- 1,6-hexanediyl) hydrochloride, also known as poly(hexamethylenebiguanide) hydrochloride (PHMB) is a cationic, polymeric guanidine antimicrobial pesticide used as a preservative of water-based materials including consumer products, as a slimicide in paper mills and industrial cooling systems, and as a sanitizer or disinfectant in livestock premises, food handling establishments, institutional settings, and pools and spas. Dietary exposure from food sources is expected. Although PHMB and its
Page 1 of 18degradates may be discharged, they are not expected to reach and/or pass through drinking water treatment plants

. Both residential and occupational exposures are likely to occur. Several additional toxicology studies are anticipated to be needed : an oral subchronic toxicity study in the rat testing the 96.3% MP; a dermal subchronic toxicity study in the rat testing the 96

.3% MP; a 90-day inhalation toxicity study in the rat testing the 20% MP and the 96

.3% MP; a developmental toxicity study in the rat testing the 96

.3% MP; and a battery of mutagenicity studies testing the 96.3% MP. The Agency intends to incorporate residue chemistry and nondietary exposure studies received in response to the PHMB post-RED DCI into the risk assessments to be performed for this registration review

. The Agency anticipates issuing the PHMB post-RED DCI in FY2013 and anticipates reviewing any data received in response to the RED DCI prior to conducting the registration review risk assessments anticipated as being needed in this scoping document. Also, the Agency notes that this registration review will be based on updated labels reflecting mitigation measures outlined in the 2004 RED and anticipated to be received through the reregistration process. The human health risk assessments expected to be necessary are: dietary risk (food only), adult residential dermal and inhalation risks from open-pour pool treatments, adult residential dermal risk from use oftreated cleaning solutions, adult residential dermal and inhalation risks from painting with treated paints (airless spray and brush/roller), adult and child residential dermal and incidental oral risks from swimming in treated pools, toddler residential dermal and incidental oral risks from playing on floors cleaned with treated cleaners, aggregate risks, occupational dermal and inhalation risks from use oftreated cleaning solutions and from painting with treated paints (airless spray and brush/roller).
Introduction The first product containing PHMB as an active ingredient was registered in the United States in 1982. PHMB is a biocidal agent used to inhibit the growth of bacteria, fungi, algae, and viruses. The mechanism of antimicrobial action is claimed to be binding to and disruption of microbial cytoplasmic membranes. There are two manufacturing
-use products (MPs), both registered to Arch Chemicals, Inc., one containing 20% ai and the other 96.3% ai. Both ofthese MPs may be used to formulate all of the end-use products (EPs). These MPs are manufactured using different processes which result in polymers of different chain lengths, molecular weights, physical/chemical properties, and, potentially, different hazards. However, the extent ofthese differences is unknown because the active ingred ients in each MP have not been fully characterized and compared. There are 22 registered EPs containing PHMB at concentrations of 0.0016-96.3% ai. A Reregistration Eligibility Decision (RED) was issued by EPA

Page 2 of 18for PHMB on 9/30/04. PHMB also has nonpesticidal uses as a preservative in cosmetics, personal care products, fabric softeners, contact lens solutions, hand washes, etc. Additionally, PHMB is used in wound/surgical dressings to prevent infection. Ofthe PHMB used in the U.S. annually, -95% is used in pools and spas (SMART meeting for 2004 RED). The Agency has conducted a screening of the available human exposure and mammalian toxicology data for PHMB as well as the current policies, use patterns, and most recent risk assessments
. The principal sources of information for this Scoping Document were the 2004 RED and documents supporting establishment of the exemption from the requirement of a tolerance in 2008 reflecting use of PHMB as a food contact surface sanitizer (73 FR 1512; 1/9/08). A 3/15/12 Web of Knowledge search of the published literature revealed no mammalian toxicity or exposure studies having been conducted since 2004. The available data are summarized below as are recommendations regarding the need for additional hazard data and the need for the conduct of human health risk assessments
. 

### Section 1. Chemical Identity and Generic Physical/Chemical Properties Table 1. Chemical**ldenti~'** 

### of PHMB.

Common Name PHMB Chemical Names Poly(iminocarbonimidoyliminocarbonimidoylimino
1,6-hexanediyl) hydrochloride; Poly(hexamethylenebiguanide) hydrochloride; Polyaminopropyl biguanide Trade Names Cosmoquil; Baquacil ; Polihexanide; Proxel; Vantocil Molecular Formula (CaH17Ns)n•xHCI Molecular Weight (183.25)n+x36.46 PC Code 111801 CAS Registry Number 32289-58-0 (27083
-27-8 in Europe) Registration Review Case No

. 3122 Chemical Structure 

# f H Hi

# ~~N"N n xHCI

PHMB is a polydisperse polymeric solid at room temperature that melts over a wide range oftemperatures (78.9-136

.3 °C). It is very soluble in water [39

.0- 43.4% (w:w) at 23

.5 °C

. The dissociation constant (PKa) is 4.19 at 25 °C. The log Potw is estimated to be -2.62 at 25 °C. The vapor pressure at 25 °C is 1.5 x 1

## o9 mmHg at 25 °C. The Henry's Law Constant is estimated to be 1.05 x 1

## o-15 atm•m3/mole at 25 °C

. · Page 3 of 18Section 2. Toxicology The test substance for all existing toxicology studies was the 20% MP (EPA Reg. No. 1258- 1252), The agency found the studies on the 20% MP (also the TGAI) to be acceptable at the time of the initial registration because the 20% MP/TGAI represented the only manufacturing process existing at the time

. The first 96

.3% product was registered in 2004. The studies conducted on the 20% MP/TGAI are still acceptable; however, additional information is necessary on the toxicity of the 96.3% MP/TGAI because its manufacturing process and properties are different than those ofthe 20% MP/TGAI.
a. Acute Toxicity In acute toxicity studies, PHMB was of low toxicity (Toxicity Category Ill) via the oral route (LDs o

# = 2747 mg/kg), dermal route (LD50 >5 mg/kg), and inhalation route (LCs o

### = 1.76 mg/L). PHMB is a severe eye and skin irritant (Toxicity Category I) and it is a moderate skin sensitizer. No additional acute toxicity data are needed for PHMB at this time

. b. Subchronic Toxicity Two 90-day subchronic oral toxicity studies were conducted, one in rats (MRID 00053460) and one in dogs (MRID 00053461). True doses on a body weight basis were not determined in the original studies or EPA reviews because it was not required at that time; doses in mg/kg/day will be calculated during the risk assessment stage ofthis registration review. In both species, the only observed effects were decreased weight gain and presence of iron pigment/hemosiderons in the liver at the highest PHMB feeding level of 5,000 ppm in rats and 11,000 ppm in dogs. In a 21-day rat dermal toxicity study (MRID 43047701) , systemic toxicity was not evident at any dose (20, 60, or 200 mg/kg/day)

. However, the dermal toxicity NOAEL was 20 mg/kg/day based on increased incidence of erythema, edema, and scabbing at the LOAEL of 60 mg/kg/day

. A limit dose resulting in adverse systemic effects was not tested because severe dermal irritation resulted at 300 mg/kg in a preliminary study

. In a human sensitization test ofVantociiiB (19

.6% PHMB), 209 volunteers began the repeated insult patch study (MRID 00127871); 191 subjects completed the study. In the induction phase ofthe study, treatment solutions were applied ten times every 2-3 days for 24 hr. In the sixth week, challenge patches were applied. The study demonstrated that PHMB can induce skin sensitization at 0.1- 0.2% v/v in the elicitation phase ofthe study. For assessing risk from exposure to treated textiles, 250 1Jg/cm2 is the 10% minimum elicitation threshold and 125 1Jg/cm2 is the study LOAEL. This study and its sensitization endpoint were used

Pa ge 4 of 18by EPA to assess certain residential risks in 2005 (EPA, 2005). See Section 10 for a discussion of human study ethics. A repeat-dose (subchronic) inhalation toxicity study is not available for PHMB. A number of PHMB use scenarios are short- and/or intermediate-term occupational and residential exposure durations. Also, a number of use scenarios result in the formation of aerosols which may be inhaled. Therefore, a 90-day inhalation toxicity study conducted with the 20% PHMB MP is needed to more fully characterize hazard and to quantify human risks via the inhalation route of exposure. c. Developmental Toxicity No quantitative or qualitative susceptibility was evident in two available prenatal developmental toxicity studies. In the rat developmental toxicity study, pregnant females received a 20% formulation of PHMB in the diet at 0, 10, 50, or 100 mg/kg/day throughout gestation. Based on reduced body weight and food consumption, the maternal toxicity LOAEL was 50 mg/kg/day. The maternal toxicity NOAEL was 10 mg/kg/day. Based on the increased incidence of ribs in fetuses, the developmental toxicity LOAEL was 100 mg/kg/day. No adverse ossification effects were observed. The developmental toxicity NOAEL was 50 mg/kg/day. In the rabbit prenatal developmental toxicity study (MRID 42865901 ), pregnant females were dosed with 20.2% PHMB via gavage at 0, 10, 20, or 40 mg/kg/day on gestation days 8-20. Based on increased mortality, reduced food consumption, and clinical signs oftoxicity, the maternal toxicity LOAEL was 40 mg/kg/day

. The maternal toxicity NOAEL was 20 mg/kg/day. The developmental toxicity LOAEL was 40 mg/kg/day, based on reduced number of litters and skeletal abnormalities (unossified 5th sternebrae, fused 3rd, 4th , and 5th sternebrae). The developmental toxicity NOAEL was 20 mg/kg/day. Although the study showed possible developmental toxicity in the form of reduced numbers of litters and skeletal abnormalities, no increased susceptibility was evident as maternal toxicity occurred at the same dose. d. Reproductive Toxicity In a 2-generation reproduction toxicity study (MRID 43617401), male and female rats received PHMB (20.2%) for 10 weeks continuously in the diet at average nominal doses of 24.6, 74.3, and 254 mg/kg/day. The parental systemic toxicity NOAEL was 74.3 mg/kg/day (avg.) based on decreased body weight and food efficiency in 

### FO males and females and decreased epididymes and kidney weight in 

### FO males at the parental systemic toxicity LOAEL of 254 mg/kg/day (avg.). There were no adverse effects of PHMB on reproduction in this study although it is noted that there was a dose-related decrease in number of pup deaths on days 1-5 postpartum for both generations. Therefore, the reproductive/systemic
Page 5 of 18toxicity NOAEL may be considered to be the high dose of 254 mg/kg/day (avg.) and the reproductive/systemic toxicity LOAEL may be considered to be greater than 254 mg/kg/day.
e. Chronic Toxicity/Carcinogenicity Three chronic/cancer studies (dog, rat, and mouse) involving dietary adm inistration of PHMB and an 80-week mouse dermal painting study are available. The data bases for chronic toxicity and carcinogen icity are conside red complete

. No additional studies are required at this time. In the 1 -year dog feeding study (MRID 43620501), male and female beagles were dosed with PHMB at 0, 7.5, 37.5, and 75 mg/kg/day (nominal levels)

. Changes in testes and liver of male dogs and clinical signs of toxicity and clinical chemistry alterations in one out offour females were elicited at 75 mg/kg/day, the LOAEL. The NOAEL was 37

.5 mg/kg/day. In the 2-year rat study (MRID 44059301), animals received PHMB in the diet at 0, 12

. 1, 36

.3, and 126.1 mg/kg/day (males) or 0, 14.9, 45.3, and 162

.3 mg/kg/day (females). There were multiple adverse effects on the liver of both sexes and decreased survival and body weight decrement in females at the LOAEL of 126.1/162.3 mg/kg/day (male/female); the NOAEL was 36.3/45.3 mg/kg/day (male/female). There was also an apparent increase in hemangiosarcomas in the liver offemale rats fed 162.3 mg/kg/day

. In a 2-year study (MRID 44074201) , mice were administered PHMB in the diet at 0, 55, 167, or 715 mg/kg/day (males) or 0, 69 , 217 , or 856 mg/kg/day (females). The system ic toxicity NOAEL was 55/69 mg/kg/day (male/female) based on the following adverse effects observed at the LOAEL of 167/217 mg/kg/day (male/female) : decreased body weight gains and non-neoplastic histopathological changes in the gall bladder, liver, and rectal-anal junction

. There was an increased incidence of liver hemangiosarcomas and squamous cell carcinomas ofthe rectal-anal junction in both sexes at 715/856 mg/kg/day (male/female). In an 80-week skin painting study (00066475 , 001 04796) , 20% PHMB was applied dermally to mice at 0, 15, 150, and 750 mg/kg/day 5 days per week. The systemic toxicity NOAEL was 1 50 mg/kg/day based on increased mortality and decreased body weight in male and female mice at the LOAEL of 750 mg/kg/day

. No compound-related tumors were observed in male mice . At the 750-mg/kg/day dose, PHMB induced an increased incidence of liver angiosarcomas in female mice

. OPP's Cancer Assessment Review Committee, in its 7/16/03 final report, classified PHMB into the category "Suggestive Evidence of Carci nogen icity, but

Page 6 of 18Not Sufficient to Assess Human Carcinogenic Potential" for inciting vascular tumors in laboratory animals by the oral and dermal routes {TXR No

. 0052040). f. Mutagenicity Acceptable mutagenicity studies including two reverse gene mutation (Ames) assays (MRID 41687004), an in vivo mouse micronucleus assay (MRID 41 096901/41404503), an in vitro cytogenetic assay (MRID 41404501/42149905), and two unscheduled DNA synthesis assays (MRID 41404502/42149903) were conducted using 19.6% PHMB as test substance. No mutagenic or genotoxic responses were observed in these studies

. g. Neurotoxicity There is no evidence of neurotoxicity, neuropathology, or histopathology of the nervous system in the available toxicity studies conducted with PHMB. Therefore, neurotoxicity data are not needed at this time

. h. Absorption, Distribution, Metabolism, and Elimination Bioavailability of PHMB was investigated in male and female rats fed diets of 10 or 100 mg/kg/day (nominal dose) for 14 days followed by a single radiolabeled dose of either 0.08 mg/kg (MRID 43567001 and 43599901) or 100 mg/kg dose (MRID 00077926 and 00086363). Feces were the major route of excretion at all dose levels, comprising greater than 90% ofthe administered dose. Similar excretion in feces was observed in bile-cannulated rats after a single radiolabeled dose of 20 mg/kg (MRID 43567001)

. Thus, fecal excretion of PHMB-derived radioactivity represents unabsorbed test material. The excretion pattern of low, mid, and high molecular weight fractions of PHMB was similar. Bioavailability was 4.7% and 3.9% for males and females, respectively, at the 10 mg/kg/day dose and 3.9% and 2

.6% for males and females, respectively, at the 100 mg/kg/day dose

. Tissue residues (total radioactivity) in rats given 10 mg/kg PHMB were 0.568 IJg/g in liver and 0.499 IJg/g in kidney of male rats. As a percentage ofthe dose, liver of male and female rats contained 0

. 18% and 0

. 19% ofthe dose, respectively, while kidneys contained 0

.03% and 0.04% ofthe dose, respectively

. Metabolite analysis of pooled urine from rats administered a low molecular weight fraction of PHMB at 20 mg/kg (the fraction showing the greatest absorption) revealed the presence of more than one metabolite but identification was not performed due to the small amount of sample available for analysis. The studies, when taken together, are acceptable to characterize the absorption, distribution, metabolism, and elimination of PHMB in rats. i. Toxicology Data Needs The inhalation route of exposure is important based on the residential and occupational uses. A 90-day rat inhalation study using the 20% PHMB MP as

Page 7 of 18test substance is needed to characterize the subchronic toxicity of PHMB and to be used to derive a hazard endpoint for the conduct of inhalation risk assessments. In order to compare the toxicity ofthe 20% MP and the 96.3% MP and determine whether they are toxicologically equivalent, the following bridging studies conducted on the 96

.3% MP are needed: an oral subchronic toxicity study in the rat; a dermal subchronic toxicity study in the rat; a 90-day inhalation toxicity study in the rat; a developmental toxicity study in the rat; and a battery of mutagenicity studies

. 

### Section 

### 3. Summary of Registered Uses PHMB is registered for a variety of antimicrobial uses as listed in Table 2. 

### T bl 2 PHMB A f

.

a e 

# . n 1m1crob" I U S 1a se ummary. Use Application Rate Application Comments (In Terms ofai) Method Adhesives, Polymer Lattices, Silicone 5000 ppm Open Pour Animal Housing/Kennels 16-5600 ppm Spray, mop, foam Cat Litter 10000 ppm Open Pour Cellulosics (Wipes, Tissues and Sponges) 40 ppm Open Pour Non-food contact Commercial, Industrial, Institutional 5000 ppm Wipe Premises Consumer Products (surface cleaners, 2500 ppm Open Pour floor cleaners, laundry detergents and fabric softeners) Dairy, Pork and Poultry Farms 200-540 ppm Spray, brush, Note 1 sponge Farm Premises and Equipment 16-5600 ppm Spra_y, mop1 foam Food and beverage processing equipment 200-540 ppm Spray, mop, wipe Note 1 and restaurants Food and beverage processing equipment 5600 ppm Spray, mop, wipe Note 2 and restaurants (EPA Reg

. No

. 71661-1) Surface Disinfectant, Medical, Non-critical 1000-5600 ppm Mop Wipe and Non-food Spray contact Industrial Cooling Water 1500 ppm Open Pour Janitorial Products, chemical toilet 5000 ppm Open Pour deodorants Leather Processing I 2600-3000 ppm Open Pour Mineral Slurries 5000 ppm Open Pour Mushroom Houses 540-5600 ppm Spray, mop, immersion Oil Drilling Muds and Fluids 3000 ppm Open Pour Paints (EPA Reg. No. 69461-1 only) 5000 ppm Open Pour Coatings 5000 ppm Open Pour Paper Mills 1500 ppm Open Pour Swimming Pools , Spas and Hot Tubs 10-20 ppm Open Pour Liquids Tablet or Cartridge Textile Spin Finish Lubricants 5000 P.Qm Open Pour Textiles (Clothing, Household Items, 40 ppm Open Pour Carpet)
Page 8 of 18

## I Tunnel Pasteurization Water 1000 ppm Open Pour 

## I Note 1 -According to the labels this product has been cleared by the EPA in 40 CFR Section 180.940(a) and (c) for use on food processing equ ipment, utensils, and other food -contact articles at a concentration of 540 or 600 ppm active. This information is in error. The actual tolerance exemption is listed in 40 CFR Section 180.1280 and it is based on 73 FR 1512 ofJan

. 9, 2008. Note 2- As perthe label, surfaces that come in contact with food , including equipment used for feeding or watering, should be rinsed with potable water before reuse when treated at this higher use dilution. Section 4. Dietary Exposure
a. Food Exposure On 1/9/08 (73 FR, No.6, p. 1512), EPA established a tolerance exemption for residues of PHMB in all foods as a result of its use as a food contact surface sanitizer in all types offood handling establishments (40 CFR 180.1280). The regulation states that PHMB formulations may be applied to food contact surfaces at up to 550 ppm in the final use dilution on food processing equipment and utensils, on dairy processing equipment, and in public eating places. It is also approved as a preservative of aqueous-based adhesives intended for use in food-contact packaging. FDA has established a threshold of regu lation for PHMB in food resulting from its use to preserve water-based latex food-contact adhesives used at :51000 ppm at :5120 oF as per 2 1 CFR 175.105

. Dietary (food) exposure is expected to result from the approved PHMB uses listed above. A dietary risk assessment was conducted by EPA in order to make a safety finding in response to the petition submitted by Arch Chem icals , Inc. in 2005 (PP#5F6975) proposing the exemption noted above. Note that these food contact uses, with a potable water rinse, had already been approved by EPA as disinfectant uses (i n the past considered to be nonfood uses) prior to submission ofthe petition

. However, in association with PP#5F6975, Arch proposed to amend their produc t labels to clearly state that a potable water rinse is not permitted for the new sanitizer uses (as opposed to an equivalent disinfectant use). In EPA 2006a, acute dietary risks to females (13-50 years) were estimated to be 19% ofthe aPAD (based on developmental effects) ; no adverse singledose effects applicable to the general population were observed. Chronic dietary risks were 16% cPAD for adult males, 19% cPAD for females (13-50) and 37% cPAD for children. To assess dietary risks resulting from current PHMB uses, the Agency intends to incorporate residue chemistry data received in response to the PHMB post-RED DCI into the risk assessments to be performed for this registration review. b. Drinking Water Exposure A quantitative drinking water assessment has not been conducted for PHMB in the past. In association with PP#5F6975, EPA concluded that drinking water exposures to PHMB would be negligible; risks were, therefore , not quantified (73 FR, No.6, p. 1512; 1/9/08). The following uses of PHMB are associated with Page 9 of 18waste water discharges that have the potentialto contaminate drinking water for consumption by humans and livestock: (i) material preservative uses; (ii) pulp and paper mill slimicide use; (iii) industrial cooling system use; (iv) sanitizer or disinfectant use in livestock premises, food handling establishments, and institutional settings; and (v) pool and spa sanitizer uses. However, as discussed in U.S. EPA 2012 (D397643), while PHMB and its degradates may be discharged, they are not expected to reach or pass through drinking water treatment plants. Therefore, assessment of human dietary risk due to PHMB residues in drinking water is not expected to be necessary based on current knowledge.
Section 5. Residential Exposure A number of pesticide products (wipes or liquid formulations) containing PHMB are labeled for residential use. Certain materials preserved or treated with PHMB, including liquid consumer products, may result in exposure of the general public and homeowners to PHMB. Preserved materials include: paints and coatings, lattices, fabric cleaning and care products, water-based cleaning products, and water-based adhesives. Activities include: spraying, mopping , and wiping treated surfaces such as floors; open-pouring 20% liquid products into pools; swimming in treated pools; toddlers crawling on treated floors; dermal contact with treated textiles including clothing; and painting with treated paint using roller, brush, and airless sprayer. Residential handler dermal and inhalation exposures to PHMB were assessed in the RED for spraying, mopping and wiping with disinfectants and open-pouring addition to swimming pools. The MOES ranged from 610 to 35,000 for dermal exposures and 3,400 to 180,000 for inhalation exposures (US EPA, 2004)

. Residential postapplication dermal and incidental oral exposures were assessed for toddlers crawling on treated floors after mopping and for adults and children swimming in treated pools. The MOEs for the treated floor scenario were 600 for dermal exposure and 660 for incidental oral exposure. The MOEs for the swimming pool scenario were all above 100,000 for dermal exposures and ranged from 230 to 3600 for incidental oral exposures. None ofthese MOEs was considered of EPA concern. An amended registration was requested in 2005 (after the RED) to add the use of PHMB to treat textiles. The exposure to treated textiles was assessed using endpoints of 250 j.Jg/cm2 (i.e. 3,800 ppm PHMB) or 125 j.Jg/cm2 (i.e. 1,000 ppm PHMB) that were derived from patch test sensitization studies on human volunteers (EPA, 2005a).The level of concern for these assessments was determined to be 1

### OX which yielded concentrations of concern for dermal sensitization (CCDS) of 25 j.Jg/cm2 (380 ppm PHMB) or 12.5 j.Jg/cm2 (1 00 ppm PHMB)

. It was determined that the leach rate of the treated textiles was less than the lowest CCDS of 12.5 j.Jg/cm2 and, therefore, the risks were not of concern for
Page 10 of 18the proposed use rate of 4000 ppm. Although this human dermal sensitization study and its endpoint were used by EPA to assess certain residential risks in 2005 (EPA, 2005a) , it has not been subjected to an ethics review or consideration by the Human Studies Review Board (HSRB). See Section 10 for a discussion of human study ethics. Residential dermal and inhalation exposures have not been assessed for PHMBtreated paints; these exposures will need to be assessed in registration review

. The residential dermal exposures arising from the uses that were assessed in the RED (i.e., swimming pools and surface cleaners) may also have to be reassessed using the human dermal sensitization effect and dose depending on the outcome ofthe ethics review. It should be noted that the dermal endpoint used in the RED, a NOAEL of 150 mg/kg/day, was based on the applied dose of 0

.3 ml oftest material that contained 2% PHMB (i

.e . 20,000 ppm). This concentration is 200 times greater than the concentration of 100 ppm PHMB that is associated with the lowest CCDS of 12

.5 mg/m3

. It is, therefore, anticipated that many of the residential exposures that were found to be of no concern in the RED would be of concern if they were assessed using the dermal sensitization endpoint. Refer to Table 3 for residential exposure scenarios that will need to be assessed during the risk assessment stage ofthis registration review.
Table 3. Residential Exposure Scenarios for PHMB. Scenario Exposure Route (s) Duration Open-pour pool treatments Dermal (Sensitization) and Inhalation Short Term Swimming in treated pools Dermal (Sensitization) Short and Intermediate Term Using treated cleaning solutions Dermal (Sensitization) and Inhalation Short and Intermediate Term Painting with treated paints Dermal (Sensitization) and Inhalation Short Term (Airless spray and brush/roller) Toddlers playing on floors cleaned with Dermal (Sensitization) and incidental Short and treated cleaning solutions oral Intermediate Term The Agency intends to incorporate human exposure studies received in response to the PHMB post-RED DCI into the risk assessments to be performed for this registration review.
Section 6. Aggregate Risk Aggregate risks were estimated as part ofthe 2004 PHMB RED (U.S. EPA 2004). Acute and chronic dietary aggregate risks were the same as the food-only risks as exposure via drinking water was not expected to occur; acute dietary risks were S9% ofthe aPAD and chronic risks were S37% ofthe cPAD

. Shortterm and intermediate-term aggregate risks were the same. Risks to children 7- 10 yr and 11-14 yr were not ofAgency concern [aggregate risk indices (ARI) of
Page 11 of 181.2-2.3]. Risks to adult males and females also were not ofAgency concern with ARis of 5.4-9.0. An ARI 2:1.0 is not ofAgency concern. Associated with PP#5F6975, EPA determined that dietary exposure from use of PHMB on food processing equipmenUutensils, dairy processing equipment, and food contact surfaces in public eating places is not likely to co-occur with exposures from other approved PHMB uses. The scenarios aggregated in the 2004 RED were considered to be much more likely to co-occur (U.S. EPA 2006c). Dietary (food) exposure is expected to occur from registered uses of PHMB. However, PHMB residues are not likely to reach drinking water as a result of industrial discharges, use in pools, water cooling systems, paper mills, etc. Residential exposure of applicators/users and postapplication exposure of adults and children to PHMB resulting from use of several end-use products or PHMBpreserved homeowner products are likely to occur. At this point, it apbears as though aggregate risk will be comprised of dietary (food) and residential sources of exposure. However, the specifics of any necessary aggregate assessments will be determined during the risk assessment stage ofthis Registration Review.
Section 7. Occupational Exposure Occupational handler dermal and inhalation exposures to PHMB were assessed in the RED for open-pour and meter pump addition scenarios for the various use patterns including material preservation, oil production, and swimming pools. The MOEs were generally not of concern except when large amounts of ai were handled as in the case of oil production for which the dermal MOE was 74 and the inhalation MOE was 370

. To mitigate the risks arising from the oil production use, it was required in the RED that labels requ ire closed system addition of PHMB; however, these changes have not yet been incorporated onto the labels. Occupational handler exposures to PHMB were also assessed in the RED for spray, mop or wipe cleaning and the MOES were not of concern; however, the dermal exposures may need to be reassessed using the dermal sensitization endpoint that was identified after the RED was completed. This endpoint is discussed under Section 5 (Residential Exposure)

. Occupational exposures have not been assessed in the past for PHMB-treated paints. In association with the label amendment to remove the potable water rinse from use on food contact surfaces, EPA assessed occupational risks (U .S. EPA 2006b). Short-term and intermediate-term hand ler risks were not ofAgency concern as the MOEs (2:2,800 for dermal and 2: 16,000 for inhalation) exceeded the level of concern of 100. Postapplication risks were not quantified because
Page 12 of 18dermal exposure was deemed to be minimal compared with handler exposures and inhalation was assumed to be negligible due to the extremely low vapor pressure of PHMB. Refer to Table 4 for the occupational exposure scenarios that will need to be assessed during the risk assessment stage ofthis Registration Review.


### Table 4. Occupational Exposure Scenarios for PHMB. Scenario Exposure Route (s) Duration Occupational Exposures Using treated cleaning solutions Dermal (Sensitization) and Inhalation Short- and IntermediateTerm Painting with treated paints Dermal (Sensitization) and Inhalation Short- and Intermed iate- (Airless sprayer and brush/roller) Term The Agency intends to incorporate human exposure studies received in response to the PHMB post-RED DCI into the risk assessments to be performed for this registration review.


### Section 8. Cumulative Risk Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism oftoxicity, EPA has not made a common mechanism oftoxicity finding as to PHMB and any other substances

. For the purposes ofthis Registration Review, therefore , EPA has not assumed that PHMB has a common mechanism oftoxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism oftoxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http ://www.epa.gov/pesticides/cumulative/.


### Section 9. Endocrine Disruption Screening Program As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive , and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence , including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation , fertility, pregnancy rates , reproductive loss, and sex ratios in offspring

. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth , developmental and reproductive effects in different taxonomic groups. As part of Page 13 of 18its reregistration decision, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), PHMB is subject to the endocrine screening part ofthe Endocrine Disrupter Screening Program (EDSP). EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a "naturally occurring estrogen, or other such endocrine effects as the Administrator may designate." The EDSP employs a two-tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage ofthe EDSP where EPA will determine which, if any, ofthe Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine-related effects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect. Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. PHMB is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data call-ins, requiring the submission of EDSP screening assays for PHMB. For further information on the status ofthe EDSP, the policies and proced ures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

. Section 10. Reliance on Human Studies Past PHMB risk assessments have relied in part on a 1981 human study that involved intentional exposure to PHMB (MRID 00127871). In the course of registration review, EPA will reconsider this study as well as consider any other research involving intentional exposure of human subjects to PHMB brought to its attention

. If EPA determines that the above intentional human exposure study is sufficiently sound from a scientific perspective to warrant inclusion in future risk assessments, EPA will consider the ethical acceptability ofthe study. Before reaching a final decision to rely on this study, EPA will ensure that all applicable regulatory requirements are met, including but not limited to the requirements for EPA ethics review and Human Studies Review Board review of certain research involving intentional exposure of human subjects.
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### Section 11. Human Incident Data A total of 118 individual incident cases submitted to the EPA Office of Pesticide Programs involving use of PHMB-containing swimm ing pool products were reviewed to determine the effects ofexposure to PHMB (CAS No

. 32289-58-0). All ofthe incident reports reflected residential use of PHMB products by consumers. Ofthe 1 18 incident cases, 17 were determined to be the result of misuse of a PHMB product. Misuse included fai ling to follow label instructions, accidental ingestion, or splashing the concentrated product onto the skin or into the eyes. The reported routes ofexposure in the 118 incident cases were dermal (58%), ocular (30%),**ing~stion** (9%), inhalation (7%) and unknown (<1 %). In some cases more than one route of exposure was applicable to an individual incident case (e

.g., both dermal and ocu lar exposure). The most common symptoms reported for each exposure route are as follows: 1. Dermal exposure: skin irritation/burning (80%), rash (50%), hives/welts (19%), itching (16%), skin discoloration/redness (9%), allerg ic reaction (7%), and blistering (7%). 2. Ocular exposu re: eye irritation/burning (1 00%), eye pain (69%), loss of vision (17%) , swelling of eyes (6%), and allergic reactions (6%). 3. Exposure via ingestion : vomiting/nausea/abdominal pain (46%), irritation to the mouth/throat (46%) , respiratory irritation including coughing/choking (18%), and diarrhea (9%)

. 4. Inhalation exposure: respiratory irritation (75%) and coughing/choking (38%). 

### Section 12. Conclusions
a. Data Needs The Agency intends to incorporate data received in response to the PHMB postRED DCI into the risk assessments to be performed for this registration review. The Agency anticipates issuing the PHMB post-RED DCI in FY2012 and anticipates reviewing any data received in response to the RED DCI prior to conducting the registration review risk assessments anticipated as being needed in this scoping document. Also, the Agency notes that this registration review will be based on updated labels reflecting mitigation measures outlined in the 2004 RED and anticipated to be received through the reregistration process.

Page 15 of 18Toxicology Data Needs The Agency recommends that the following toxicology studies be conducted :
• 90-Day Rat Inhalation Toxicity in the rat testing the 20% MP and the 96.3% MP (GLN 870.3465) • 90-Day Oral toxicity study in the rat testing the 96.3% MP (GLN 870.3100) • Developmental toxicity study in the rat testing the 96.3% MP (GLN 870.3700) • 90-Day dermal toxicity study in the rat testing the 96.3% MP (GLN 870.3250) • Mutagenicity battery testing the 96.3% MP (GLN 870.5375, 870.5395, 870.5550) Residential/Occupational Exposure Data Needs The Agency intends to incorporate human exposure data received in response to the PHMB post-RED DCI into the residential and occupational risk assessments to be performed for this registration review. Residue Chemistry Data Needs The Agency intends to incorporate residue chemistry data received in response to the PHMB post-RED DCI into the dietary risk assessments to be performed for this registration review. b. Risk Assessments Needed
• A dietary (food) risk assessment will be needed to reflect use of PHMB as a food contact surface disinfectant at the higher rate (5,600 ppm) with a potable water rinse in all types offood handling establishments and as a preservative of aqueous-based adhesives intended for use in food contact packaging

. • Residential applicator/user dermal and inhalation risks to adults from exposure to PHMB residues while painting with preserved paint using airless sprayer and brush/roller. • Residential applicator/user dermal and inhalation risks to adults from exposure to PHMB residues while: (i) open-pouring pool treatments ; (ii) swimming in treated pools; and (iii) using treated cleaning solutions. • Residential postapplication dermal and incidental oral risks to chi ldren from exposure to PHMB residues whi le playing on floors cleaned with treated clean ing solutions. • At this poi nt, it appears as though aggregate risk will consist of dietary (food only) and residential exposure sources. However, the details of any needed aggregate assessments will be determined during the risk assessment stage ofthis Registration Review. Page 16 of 18• Occupational handler dermal and inhalation risks from PHMB exposure while painting with treated paints using airless sprayer and brush/roller. • Occupational handler dermal and inhalation risks resulting from the use of treated cleaning solutions. • Depending on the outcome ofthe ethics review, all dermal assessments may need to be repeated using the human dermal sensitization endpoint.


### c. Label and Tolerance Issues
• Labels for EPA Reg. Nos

. 1258- 1324 and 1258- 1335 (Arch Chemicals, Inc.) should be revised by deleting mention of PHMB having EPAestablished exemptions at 40 CFR 180.940(a) and -(c). If desired, the registrant may, instead, refer to 40 CFR 180

. 1280. • The labels need to be updated to include the closed-system requirement for oil field uses specified by the RED. • FDA has approved PHMB as a preservative of aqueous-based adhesives intended for use in food
-contact packaging. FDA has established a threshold of regulation for PHMB in food resulting from its use to preserve water-based latex food-contact adhesives used at s;1 000 ppm at s;120 oF as per 21 CFR 175.105. Any label bearing th is use should state that "preserved water-based adhesives may be used for food-contact purposes."


### Section 13. References U

.S. EPA. 2004. Registration Eligibility Decision (RED) for Poly(hexamethylenebiguanide) hydrochloride, United States Environmental Protection Agency, August 1996 U.S

. EPA. 2005a

. Post-Application Dermal Exposure Assessment in Support of Proposed Amended Registration for Vantocil 1 B Microbiocide to Add New Uses for Treating Fabrics/Apparel. June 1, 2005. D313871. U.S. EPA. 2005b. Hazard Assessment of the Dermal Sensitization Potential of PHMB- report ofthe Antimicrobials Division Toxicity Endpoint Selection Committee (ADTC) , Apri l 25, 2005. D313872. U.S

. EPA. 2006a

. Review of Pesticide Petition 5F6975 and for Registration #1258-1252 for Residues Resulting in/on Food from a PHMB Sanitizer Use. July 5 , 2006. Review by R. Quick

. D320916

. U.S. EPA. 2006b. Occupational Exposure Assessment for VANTOCIL® IB Microbiocide: New Use of a Sanitizer in Food Handling/Storage Establishments, Premises and Equipment, Including Food Contact Surfaces in Public Eating Places, Dairy Processing Equipment and Food Processing Equipment and Page 17 of 18Utensils. EPA Reg istration No. 1258-153, August 24, 2006. 0323898 and 0323900

. U.S. EPA. 2006c. Aggregate Risk Assessment for VANTOCIL 

### 18 Microbiocide: New Use as a Sanitizer, EPA Reg istration No. 1258-1253. September 26, 2006

. Review by Talia Mi lano. 0323897 and 0323899. U.S

. EPA. 2012. Product Chemistry, Environmental Fate, and Ecological Effects Seeping Document in Support of Registration Review of Poly(hexamethylenebiguanide) hydrochloride

. Review by S. Gowda, D

. Randall, and N. Shamim

. April, 2012. 0397643. Smith, I. (1981) Human Sensitisation Testing ofVontociiiB: ISC Report No

. 0018

. Final rept. (Unpublished study received Mar 17, 1982 under 10182-19; prepared by lan Sm ith Consultancy, Eng., submitted by ICI Americas, Inc., Wilmington, DE; COL: 247255-A). MRID 00127871.

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