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

6/27/12

MEMORANDUM

SUBJECT:

PC Code: 111801 OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

Poly(hexamethylenebiguanide) hydrochloride. Human Health Scoping Document for the Registration Review.

Decision No.: 459594
Petition No s .: NA

Risk Assessment T

TXR No.: NA

MRID Nos.: NA

FROM:

TO:

THRU: Re ulato Action: Re istration Review

Ie chemical Re istration Review Case No .: 3122
CAS No

. : 32289-58-0

40 CFR: 180.1280

William J. Hazel, Ph

. D., Chemist,**Scie~c rdinat**  Michelle Centra,

### Pharmacologist**~~** 

# ;/k(

Timothy Dole, CIH, Industrial Hygienist (t;: ' .."."\A4

...... , .,. Jonathan Chen, Ph.D., Incident Data**"-- ~~~**  Risk Assessment and Science Support Branch (RASSB)

Antimicrobials Division (7510P)

Rebecca von dem-Hagen, Chemical Review Manager Regulatory Management Branch II

Antimicrobials Division (7510P)

Jonathan Chen, Ph

. D., Acting Chief

## ~**~** Timothy Leighton, Senior ScientistfTeam Leader

### ~~ Risk Assessment and Science Support Branch (RASSB)

Antimicrobials Division (7510P)

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 degradates may be discharged, they are not expected to reach and/or pass

Page 1 of 18Page 2 of 18 through drinking water treatment plant s. Both residential and occupational exposures are likely to occur.

One additional toxicology study (90-day inhalation toxicity) is anticipated to be needed. The Agency intends to incorporat e 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 FY 2012 and anticipates reviewing any data received in response to the RED DCI prio r to conducting the registration review risk assessments anticipated as being nee ded in this scoping document. Also, the Agency notes that this registrati on 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 fr om use of treated 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 in halation risks from use of treated 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 me chanism 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. There are 22 registered end-use products (EPs) containi ng PHMB at concentrations of 0.0016- 96.3% ai. A Reregistration Eligibility Decision (RED) was issued by EPA for 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. Of the 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 assessment s. The principal sources of information for this Scoping Document were the 2004 RED and do cuments supportingPage 3 of 18 establishment of the exem ption from the requirement of a tolerance in 2008 reflecting use of PHMB as a food contac t surface sanitizer (73 FR 1512; 1/9/08).

A 3/15/12 Web of Knowle dge search of the publis hed literature revealed no mammalian toxicity or exposure studies having been conducted since 2004. The

available data are summa rized below as are reco mmendations 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 Identity of PHMB.

Common Name PHMB

Chemical Names Poly(iminocarbonimidoyliminocarbonimidoylimino1,6-hexanediyl) hydrochloride; Poly(hexamethylenebigua nide) hydrochloride;

Polyaminopropyl biguanide

Trade Names Cosmoquil; Baquacil; Po lihexanide; Proxel; Vantocil Molecular Formula (C 8 H 17 N 5 )
n •xHCl 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

PHMB is a polydisperse polymeric solid at room temperature that melts over a wide range of temper atures (78.9-136.3 o C). It is very soluble in water [39.0- 43.4% (w:w) at 23.5 o C. The dissociation constant (pK
a ) is 4.19 at 25 o C. The log

P o/w is estimated to be -2.62 at 25 o C. The vapor pressure at 25 o C is 1.5 × 10 -9
mmHg at 25 o C. The Henry's Law Constant is estimated to be 1.05 x 10 -15

atm•m 3 /mole at 25 o C.

Section 2. Toxicology

a. Acute Toxicity

In acute toxicity studies, PHMB was of low toxicity (Toxicity Category III) via the oral route (LD 50 = 2747 mg/kg), dermal route (LD 50 >5 mg/kg), and inhalation route (LC 50 = 1.76 mg/L). PHMB is a severe eye and skin irritant (ToxicityPage 4 of 18 Category I) and it is a moder ate skin sensitizer. No additional acute toxicity data

are needed for PHMB at this time.

b. Subchronic Toxicity

Two 90-day subchronic oral toxicity studi es 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 of this 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 (MR ID 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 increas ed 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 of Vantoc il IB (19.6% PHMB), 209 volunteers began the repeated insult patch study (MRI D 00127871); 191 subjects completed the study. In the induction phase of the study, treatment solutions were applied ten times every 2-3 days for 24 hr. In t he 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 of the study. For assessing risk from exposure to treated textiles, 250 μg/cm 2 is the 10% minimum elicitation threshold and 125 μg/cm 2 is the study LOAEL. This study and its sensitization endpoint were used by EPA to assess certain residential risks in 2005 (EPA, 2005). See Section 10 for a discussion of human study ethics.

A repeat-dose (subchronic) inhal ation 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 inha led. Therefore, a 90-day inhalation toxicity study conducted with PHMB is needed to more fully characterize hazard and to quantify human risks via the i nhalation 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 PH MB in the diet at 0, 10, 50, or 100 mg/kg/day throughout gestation. Bas ed on reduced body weight and food consumption, the maternal toxicity LOAEL was 50 mg/kg/day. The maternalPage 5 of 18 toxicity NOAEL was 10 mg/kg/day. Bas ed on the increased incidence of ribs in fetuses, the developmental toxicity LOAEL was 100 mg/kg/day. No adverse

ossification effects were observed. T he developmental toxicity NOAEL was 50 mg/kg/day.

In the rabbit prenatal developmental to xicity 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 of toxici ty, 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 5 th sternebrae, fused 3 rd , 4 th , and 5 th
sternebrae). The developmental toxicity NO AEL was 20 mg/kg/day. Although the study showed possible developmental toxici ty in the form of reduced numbers of litters and skeletal abnormalities, no in creased 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/k g/day. The parental systemic toxicity NOAEL was 74.3 mg/kg/day (avg.) bas ed on decreased body weight and food efficiency in F0 males and females and decreased epididymes and kidney weight in F0 males at the parent al 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. T herefore, the repr oductive/systemic toxicity 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

administration of PHMB and an 80-week mouse dermal painting study are

available. The data bases for chronic to xicity and carcinogenicity are considered 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).

C hanges in testes and liver of male dogs and clinical signs of toxicity and clinical chemistry alterations in one out of four females were elicited at 75 mg/kg/day, the LOAEL. The NOAEL was 37.5 mg/kg/day.Page 6 of 18 In the 2-year rat study (MRID 44059301), animals receiv ed 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 advers e effects on the liver of both sexes and decreased survival and body weight decre ment in females at the LOAEL of 126.1/162.3 mg/kg/day (male/fe male); the NOAEL was 36.3/45.3 mg/kg/day (male/female). There was also an apparent increase in hemangiosarcomas in the liver of female rats fed 162.3 mg/kg/day.

In a 2-year study (MRID 44074201), mice we re 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 systemic 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, an d rectal-anal junction.

There was an increased incidence of liver hemangiosarcomas and squamous

cell carcinomas of the re ctal-anal junction in both sexes at 715/856 mg/kg/day (male/female).

In an 80-week skin painting study (00066475, 00104796), 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 150 mg/k g/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 observe d in male mice. At the 750-mg/kg/day dose, PHMB induced an increased incidenc e of liver angiosarcomas in female

mice.

OPP’s Cancer Assessment Review Co mmittee, in its 7/16/03 final report, classified PHMB into the category “Sugges tive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic Potential” for inciting vascular tumors in laboratory animals by the or al and dermal routes (TXR No. 0052040).

f. Mutagenicity

Acceptable mutagenicity studies includi ng two reverse gene mutation (Ames) assays (MRID 41687004), an in vivo mouse micronucleus assay (MRID 41096901/41404503), an in vitro cytogenetic assay (MR ID 41404501/42149905), and two unscheduled DNA synthesis assa ys (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, neurotoxic ity data are not needed at this time.Page 7 of 18 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 ma jor route of excretion at all dose levels, comprising greater than 90% of the 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 radioactivit y represents unabsorbed test material. The excretion pattern of low, mid, and high molecular we ight fractions of PHMB was similar. Bioavailability was 4.7% and 3.9% for ma les and females, respectively, at the 10 mg/kg/day dose and 3.9% and 2.6% for male s and females, respectively, at the 100 mg/kg/day dose. Tissue residues (total radioactivity) in rats given 10 mg/kg PHMB were 0.568 μg/g in liver and 0.499 μg/g in kidney of male rats. As a percentage of the dose, liver of male and female rats contained 0.18% and 0.19% of the dose, respectively, while kidneys contained 0.03% and 0.04% of the dose, respectively. Metabolite analysis of pooled urine from rats administered a low molecular weight fraction of PHMB at 20 mg/kg (the fr action showing the greatest absorption) revealed the pres ence of more than one metabolite but identification was not perform ed 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 PHMB as test substance is needed to characterize the subchronic toxicity of PHMB and to be used to derive a hazard endpoint for the conduc t of inhalation risk assessments.

Section 3. Summary of Registered Uses

PHMB is registered for a variety of antimicrobial uses as listed in Table 2.

Table 2. PHMB Antimi crobial Use Summary.

Use Application Rate (In Terms of ai) Application

Method Comments

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

Premises 5000 ppm Wipe

Consumer Products (surface cleaners, floor cleaners, laundry detergents and 2500 ppm Open PourPage 8 of 18 fabric softeners) Dairy, Pork and Poultry Farms 200-540 ppm Spray, brush,

sponge Note 1

Farm Premises and Equipment 16-5600 ppm Spray, mop, foam Food and beverage processing equipment

and restaurants 200-540 ppm Spray, mop, wipe Note 1

Food and beverage processing equipment

and restaurants (EPA Reg. No. 71661-1) 5600 ppm Spray, mop, wipe Note 2

Surface Disinfectant, Medical, Non-critical 1000-5600 ppm Mop Wipe and Spray Non-food

contact
Industrial Cooling Water 1500 ppm Open Pour
Janitorial Products, chemical toilet

deodorants 5000 ppm Open Pour

Leather Processing 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 ppm Open Pour Textiles (Clothing, Household Items, Carpet) 40 ppm Open Pour

Tunnel Pasteurization Water 1000 ppm Open Pour

Note 1 – According to the labels this product has been cl eared by the EPA in 40 CFR Section 180.940(a) and (c) for use on food processing equipment, utensils, and other food - contact ar ticles 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 of Jan. 9, 2008. Note 2 – As per the label, surfaces that come in contac t 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 resu lt of its use as a food contact surface sanitizer in all types of food handling establishments (40 CFR 180.1280). The regulation states that PHMB formula tions 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 proc essing 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 regulation for PHMB in food resulting from its use to pr eserve water-based latex food-contact

adhesives used at ≤ 1000 ppm at ≤ 120 °F as per 21 CFR 175.105.

Dietary (food) exposure is expected to result from the approved PHMB uses listed above. A dietary risk assessment wa s conducted by EPA in order to makePage 9 of 18 a safety finding in response to the petition submitted by Arch Chemicals, Inc. in 2005 (PP#5F6975) proposing t he exemption noted above. Note that these food contact uses, with a potable water rins e, had already been approved by EPA as disinfectant uses (in the past consider ed to be nonfood uses) prior to submission of the petition. However, in associat ion with PP#5F6975, Arch proposed to amend their product labels to clearly stat e that a potable water rinse is not permitted for the new sanitizer uses (a s opposed to an equivalent disinfectant use). In EPA 2006a, acute dietary risks to females (13-50 years) were estimated to be 19% of the aPAD (based on devel opmental effects); no adverse singledose effects applicable to the general popu lation 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 cu rrent PHMB uses, the Agency intends to incorporate residue chemistry data receiv ed in response to the PHMB post-RED DCI into the risk assessments to be per formed 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 waste water discharges that have the potential to contaminate drinking water for consumption by humans and livestock: (i) ma terial preservative uses; (ii) pulp and paper mill slimicide use; ( iii) industrial cooling system use; (iv) sanitizer or disinfectant use in livestock premis es, 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. Therefor e, assessment of human di etary risk due to PHMB residues in drinking water is not ex pected 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 cons umer products, may result in exposure of the general public and homeowners to PHMB. Preser ved materials include: paints and coatings, lattices, fabric cleaning and care products, water-based cleaning products, and water-based adhesives. Activiti es include: spraying, mopping, and wiping treated surfaces such as floor s; open-pouring 20% liquid products into pools; swimming in treated pools; toddler s crawling on treated floors; dermalPage 10 of 18 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, m opping and wiping with disinf ectants 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 inci dental oral exposures were assessed for toddlers crawling on treated floors a fter 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 of these 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 μg/cm 2 (i.e. 3,800 ppm PHMB) or 125 μg/cm 2 (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 10X which yielded c oncentrations of concern for dermal sensitization (CCDS) of 25 μg/cm 2 (380 ppm PHMB) or 12.5 μg/cm 2 (100 ppm PHMB). It was determined that the leach rate of the tr eated textiles was less than the lowest CCDS of 12.5 μg/cm 2 and, therefore, the risks we re not of concern for the proposed use rate of 4000 ppm. Alt hough 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 subj ected to an ethics review or consideration by the Human Studies Revi ew 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 exposu res will need to be assessed in registration review. The residential dermal exposures arising fr om the uses that were assessed in the RED (i.e., swimming pools and surfac e cleaners) may also have to be reassessed using the human dermal sensit ization effect and dose depending on

the outcome of the ethics review. It should be noted that the dermal endpoint used in the RED, a NOAEL of 150 mg/k g/day, was based on the applied dose of

0.3 mL of test material that cont ained 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/m 3 . It is, therefor e, anticipated that many of the residentia l 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 st age of this registration review.Page 11 of 18 Table 3. Residential Expos ure 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 (Airless spray and brush/roller) Dermal (Sensitization) and Inhalation Short Term

Toddlers playing on floors cleaned with treated cleaning solutions Dermal (Sensitization) and incidental

oral Short and

Intermediate Term

The Agency intends to incorporate human exposure studies received in response to the PHMB post-RED DCI into the ri sk assessments to be performed for this registration review.

Section 6. Aggregate Risk

Aggregate risks were estimated as part of the 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 ≤ 9% of the aPAD an d chronic risks were ≤ 37% of the cPAD. Shortterm and intermediate-term aggregate risks were the same. Risks to children 7- 10 yr and 11-14 yr were not of Agency c oncern [aggregate risk indices (ARI) of 1.2-2.3]. Risks to adult males and females also were not of Agency concern with

ARIs of 5.4-9.0. An ARI ≥ 1.0 is not of Agency concern.

Associated with PP#5F6975, EPA determined that dietary expos ure from use of PHMB on food processing equipment/ut ensils, dairy processing equipment, and food contact surfaces in public eating places is not likely to co-occur with exposures from other approved PHMB us es. 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, wate r cooling systems, paper mills, etc. Residential exposure of applic ators/users and postapplicat ion 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 appears as though aggregat e risk will be comprised of dietary (food) and residential source s of exposure. However, the specifics of any necessary aggregate assessments will be determined during the risk assessment stage of this Registration Review.Page 12 of 18 Section 7. Occ upational Exposure

Occupational handler dermal and inhalati on exposures to PHMB were assessed in the RED for open-pour and meter pump addi tion scenarios for the various use patterns including material preservation, oil production, and swimming pools. The MOEs were generally not of concern ex cept 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 t he RED that labels require 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 Ex posure). 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 handler risks were not of Agency concern as the MOEs ( ≥ 2,800 for dermal and ≥ 16,000 for inhalation) exceeded

the level of concern of 100. Postapplication risks were not quantified because dermal exposure was deemed to be mini mal compared with handler exposures and inhalation was assumed to be negligib le due to the extremely low vapor pressure of PHMB. Refer to Table 4 for the occupati onal exposure scenarios that will need to be assessed during the risk a ssessment stage of this 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

Intermediate-Term Painting with treated paints (Airless sprayer and brush/roller) Dermal (Sensitization) and Inhalation Short- and

Intermediate-Term

The Agency intends to incorporate human exposure studies received in response to the PHMB post-RED DCI into the ri sk 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 of toxicity, EPA has not made a common mechanism of toxicity finding as to PH MB and any other substances. For thePage 13 of 18 purposes of this Registration Review, therefore, EPA has not assumed that

PHMB has a common mechanism of to xicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to eval uate 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 Disr uption 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 chr onic toxicity, including assessments of carcinogenicity, neurotoxicity, devel opmental, 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 cyclic ity, 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 its reregistration decision, EPA reviewed thes e 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 of the Endocrine Disr uptor 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 Admi nistrator may designate.” The EDSP employs a two-tiered approach to making t he statutorily requi red 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 of the EDSP where EPA will det ermine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine-related e ffects 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 i ssued test orders/data call-ins for the first group of 67 chem icals, which contains 58 pesticide active ingredients and 9 inert ingredients. PHMB is not among the group of 58 pesticide activePage 14 of 18 ingredients on the initial list to be screened u nder 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 furt her information on the status of the EDSP, the policies and procedures, th e 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 t he above intentional human exposure study is sufficiently sound from a scientific perspec tive to warrant inclusion in future risk assessments, EPA will consider the ethica l acceptability of the study. Before reaching a final decision to rely on th is study, EPA will ensur e that all applicable regulatory requirements are met, including but not limited to the requirements for

EPA ethics review and Human Studies Revi ew Board review of certain research involving intentional ex posure of human subjects.

Section 11. Human Incident Data

A total of 118 individual incident cases submitted to the EPA Office of Pesticide Programs involving use of PHMB-cont aining swimming pool products were

reviewed to determine the e ffects of exposure to PHMB (CAS No. 32289-58-0). All of the incident report s reflected residential use of PHMB products by

consumers. Of the 118 inci dent cases, 17 were determined to be the result of misuse of a PHMB product. Misuse included failing to follow label instructions, accidental ingestion, or splashing the c oncentrated product onto the skin or into the eyes.

The reported routes of exposure in t he 118 incident cases were dermal (58%), ocular (30%), ingestion (9%), inhalat ion (7%) and unknown (<1%). In some cases more than one route of exposure wa s applicable to an individual incident case (e.g., both dermal and ocular ex posure). The most common symptoms reported for each exposure route are as follows:

1. Dermal exposure: skin irritation/bur ning (80%), rash (50%), hives/welts (19%), itching (16%), skin discolora tion/redness (9%), allergic reaction (7%), and blistering (7%).

2. Ocular exposure: eye irritation/ burning (100%), eye pain (69%), loss of vision (17%), swelling of eyes (6 %), and allergic reactions (6%).Page 15 of 18 3. Exposure via ingestion: vomiting/naus ea/abdominal pain (46%), irritation to the mouth/throat (46% ), respiratory irritation including coughing/choking (18%), and diarrhea (9%).

4. Inhalation exposure: respirator y 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 not es that this registration review will be based on updated labels reflecting mitigation measures out lined in the 2004 RED and anticipated to be received through the reregistration process.

Toxicology Data Needs

The Agency recommends that the followi ng toxicology study be conducted using PHMB as test substance (utility and rationale provided in Appendix A):

 90-Day Rat Inhalation Toxicity (GLN 870.3465)

Residential/Occupational Exposure Data Needs

The Agency intends to incorporate human exposure data received in response to the PHMB post-RED DCI into the resi dential 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 diet ary 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 of food handling establishments and as a preservative of aqueous-based adhesives intended for use in food contact packaging.Page 16 of 18  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 children from exposure to PHMB residues wh ile playing on floors cleaned with treated cleaning solutions.

 At this point, it appears as though aggregate risk will consist of dietary (food only) and residential exposure sour ces. However, the details of any needed aggregate assessm ents will be determi ned during the risk assessment stage of this Registration Review.

 Occupational handler dermal and inhal ation risks from PHMB exposure while painting with treated paints usi ng airless sprayer and brush/roller.

 Occupational handler dermal and inhalat ion risks resulting from the use of treated cleaning solutions.

 Depending on the outcome of the et hics review, all dermal assessments may need to be repeated using the hum an 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 deletin g 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 incl ude 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 f ood resulting from its use to preserve

water-based latex food-contact adhesives used at ≤ 1000 ppm at ≤ 120 °F as per 21 CFR 175.105. Any label bear ing this 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 Environm ental Protection Agency, August 1996

U.S. EPA. 2005a. Post-Application Derma l Exposure Assessment in Support of Proposed Amended Registration for Vantocil 1B Microbiocide to Add New Uses for Treating Fabrics/Apparel. June 1, 2005. D313871.Page 17 of 18 U.S. EPA. 2005b. Hazard Assessment of t he Dermal Sensitization Potential of PHMB – report of the An timicrobials Division Toxicity Endpoint Selection Committee (ADTC), Apr il 25, 2005. D313872.

U.S. EPA. 2006a. Review of Pesticide Pe tition 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 Exposur e Assessment for VANTOCIL® IB

Microbiocide: New Use of a Sanitizer in Food Handling/Storage Establishments, Premises and Equipment, Including Food C ontact Surfaces in Public Eating Places, Dairy Processing Equipment and Food Processing Equipment and Utensils. EPA Registration No. 1258-153, August 24, 2006. D323898 and

D323900.

U.S. EPA. 2006c. Aggregate Risk Assessment for VANTOCIL IB Microbiocide: New Use as a Sanitizer, EPA Registra tion No. 1258-1253. September 26, 2006. Review by Talia Milano. D323897 and D323899.

U.S. EPA. 2012. Product Chemistry, Environmental Fate, and Ecological Effects Scoping Document in Support of Regist ration Review of Poly(hexamethylenebiguanide) hydrochloride. Review by S. Gowda, D. Randall, and N. Shamim. April, 2012. D397643.

Smith, I. (1981) Human Sensitisation Testing of Vontocil IB: ISC Report No. 0018. Final rept. (Unpublished study received Mar 17, 1982 under 10182-19; prepared by Ian Smith Consul tancy, Eng., submitted by ICI Americas, Inc., Wilmington, DE; CDL: 247255-A). MRID 00127871.Page 18 of 18 Appendix A

I. Need for, and Uses of, the Data

Guideline Number: 870.3465 Study Title: 90-Day Inhalation Toxicity (Rat) Rationale for Requiring the Data

This study is required because several use scenarios involve generation of aerosols (such as painting). Also, respirable dust may be created by ev aporation of the solvent from fine to medium spray droplets because PHMB is a nonvolatile salt. There is a likelihood of significant repeated inhalation exposure to homeowners and occupational handlers using direct-pour methods and breathing aerosols or dust during or after use/application of materials preserved with PHMB, especially while painting with preserved paint or coatings. Many preserved homeowner, commercial, and institutional liquid spray products are preserved with PHMB and will result in significant inhalation exposure professionally and in the home. A 90-day inhalation toxicity study has not been conducted and is needed. The inhalation route is the major route of human exposure to PHMB per se for a number of scenarios. A route-specific (subchronic) toxi city study is critical for proper characterization and quantification of hazard and risk to human health from inhalation exposures to PHMB. Practical Utility of the Data 1. How did the Agency make its earlier regulatory decisions without these data?

Earlier regulatory decisions were based on inhalati on risks using a hazard endpoint derived from oral toxicity studies. As a major exposure route is inhalation and a subchronic inhalation toxicity study is not available, there is no route-specific study to appropriately use in a quantitative risk assessment reflecting the inhalation route of exposure.

2. How will the data be used?

The data will be used to properly characterize and quantify the inhalation hazard and risks to occupational workers as well as residential adults while painting, spraying treated cleaners, etc. This study may also provide a dose and toxicological endpoint applicable to a quantitative inhalation risk assessment. A repeat-dose inhalation toxicity study can be designed to simulate both a real world route of human exposure as well as a specific duration of exposure to varying (aerosol) concentrations of the test material. A detailed toxicological examination including the histopathology of the respiratory system would also be conducted in an inhalation toxicity study and thereby provide a better understanding of potential adverse effects resulting from exposure to PHMB via the

inhalation route.

3. How could the data impact the Agency’s future decision-making?

In the absence of inhalation toxicity data, the Agency would now have to estimate inhalation risks using an oral toxicity study and rely on the assumption that absorption and toxicity of PHMB are the same via the oral and inhalation routes of exposure. Absorption of pesticides into the bloodstream via the lungs may be higher than that via the dietary route resulting in a different toxicity profile for different routes of exposure. Paired with the requested chemical-specific PHMB inhalation exposure data, the route-specific 90-day rat inhalation to xicity study using PHMB will permit EPA to conduct residential and occupational risk assessments that are refined and in which there is a high degree of

confidence.