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 

Timothy Leighton, 

Chen, Ph

Senior 

.D., Acting 

ScientistfTeam 

Chief ~ 

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 18 
 Page 2 of 18

through drinking water treatment plants. 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 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 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. 

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 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 inhalation 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 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. There are 22 

registered end-use products (EPs) containing 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 assessments. The principal sources of information 

for this Scoping Document were the 2004 RED and documents supporting 
 Page 3 of 18

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 Identity of PHMB. 

Common Name PHMB 

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

Poly(hexamethylenebiguanide) hydrochloride; 

Polyaminopropyl biguanide 

Trade Names Cosmoquil; Baquacil; Polihexanide; Proxel; Vantocil 

Molecular Formula (C8H17N5)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 temperatures (78.9-136.3 oC). It is very soluble in water [39.0-

43.4% (w:w) at 23.5 oC. The dissociation constant (pKa) is 4.19 at 25 oC. The log 

Po/w is estimated to be -2.62 at 25 oC. The vapor pressure at 25 oC is 1.5 × 10-9

mmHg at 25 oC. The Henry's Law Constant is estimated to be 1.05 x 10-15

atm•m3/mole at 25 oC. 

Section 2. Toxicology 

a. Acute Toxicity 

In acute toxicity studies, PHMB was of low toxicity (Toxicity Category III) via the 

oral route (LD50 = 2747 mg/kg), dermal route (LD50 >5 mg/kg), and inhalation 

route (LC50 = 1.76 mg/L). PHMB is a severe eye and skin irritant (Toxicity 
 Page 4 of 18

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 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 (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 of Vantocil IB (19.6% PHMB), 209 volunteers began 

the repeated insult patch study (MRID 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 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 of the study. For assessing risk from exposure to 

treated textiles, 250 μg/cm2

 is the 10% minimum elicitation threshold and 125 

μg/cm2 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) 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 PHMB 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 
 Page 5 of 18

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 of toxicity, 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 F0 males and females and decreased epididymes and kidney weight 

in F0 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 

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 toxicity 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).

Changes 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 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 of female 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 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, and rectal-anal junction. 

There was an increased incidence of liver hemangiosarcomas and squamous 

cell carcinomas of the rectal-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/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 Carcinogenicity, but 

Not 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 

41096901/41404503), 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. 
 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 major 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 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 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 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 PHMB as test 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. 

Section 3. Summary of Registered Uses 

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

Table 2. PHMB Antimicrobial 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 Pour
 Page 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 cleared by the EPA in 40 CFR Section 180.940(a) and (c) for use 

on food processing equipment, 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 of Jan. 9, 2008. 

Note 2 – As per the 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 of food 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 regulation for PHMB 

in food 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. 

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 
 Page 9 of 18

a safety finding in response to the petition submitted by Arch Chemicals, 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 (in the past considered to be nonfood uses) prior to submission 

of the petition. However, in association with PP#5F6975, Arch proposed to 

amend their product 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% of the 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 

waste water discharges that have the potential to 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 
 Page 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, 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 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/cm2

 (i.e. 3,800 ppm PHMB) or 125 μg/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 10X which yielded concentrations of concern for dermal 

sensitization (CCDS) of 25 μg/cm2

 (380 ppm PHMB) or 12.5 μg/cm2 (100 ppm 

PHMB). It was determined that the leach rate of the treated textiles was less than 

the lowest CCDS of 12.5 μg/cm2 and, therefore, the risks were not of concern for 

the 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 of the 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 of test 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 of this registration review. 
 Page 11 of 18

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 

(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 risk 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 and 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 concern [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 exposure from use of 

PHMB on food processing equipment/utensils, 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 appears 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 of this Registration Review. 
 Page 12 of 18

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 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 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 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 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 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 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 of toxicity, EPA has not made a common 

mechanism of toxicity finding as to PHMB and any other substances. For the 
 Page 13 of 18

purposes of this Registration Review, therefore, EPA has not assumed that 

PHMB has a common mechanism of toxicity with other substances. For 

information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity 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 

its 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 of the Endocrine Disruptor 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 of the EDSP where EPA will determine 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 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 
 Page 14 of 18

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 of the EDSP, the policies and procedures, 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 of the 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. 

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 swimming pool products were 

reviewed to determine the effects of exposure to PHMB (CAS No. 32289-58-0). 

All of the incident reports reflected residential use of PHMB products by 

consumers. Of the 118 incident 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 concentrated product onto the skin or into 

the eyes. 

The reported routes of exposure in the 118 incident cases were dermal (58%), 

ocular (30%), ingestion (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 ocular 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%), 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/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. 

Toxicology Data Needs

The Agency recommends that the following 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 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 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 while 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 sources. However, the details of any 

needed aggregate assessments will be determined during the risk 

assessment stage of this Registration Review. 

 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 of the 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 ≤1000 ppm at ≤120 °F 

as per 21 CFR 175.105. Any label bearing 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 Environmental Protection Agency, 

August 1996 

U.S. EPA. 2005a. Post-Application Dermal 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 the Dermal Sensitization Potential of 

PHMB – report of the Antimicrobials Division Toxicity Endpoint Selection 

Committee (ADTC), April 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 

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 Registration 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 Registration 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 Consultancy, 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 evaporation 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) toxicity 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 inhalation 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 toxicity 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.