United States Chemical Safety September 2011

Environmental Protection and Pollution Prevention

Agency (7510P)

Chlorhexidine Derivatives

Registration Review:

Final Work Plan

September 2011
Docket Number: EPA-HQ-OPP-2011 -0069 

www.regulations.gov 

Chlorhexidine Derivatives 

Registration Review: 

Final Work Plan 

September 2011 

Case # 3038 

Approved By: 

t}S

Il

irector, 

an Harrigan-Farrelly 

Antimicrobials Division 

~ 

Date: 

o i/o :z!AJ// I 7 

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Chlorhexidine Derivatives Registration Review Team

Michelle Centra

Human Health & Environmental Effects

Timothy Dole

Srinivas Gowda

Rebecca von dem Hagen

Risk Management

Lance Wormell

Philip Ross

Office of General Counsel

________________________________________

Supporting documents for the Chlorhexidine Derivatives Case may be found in the registration 

review docket EPA-HQ-OPP-2011-0069 located on the internet at www.regulations.gov.
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This is the Final Work Plan (FWP) of the Environmental Protection Agency (EPA or “the 

Agency”) for the registration review of chlorhexidine derivatives (Case 3038). The work plan 

includes the expected registration review timeline. The work plan also addresses public 

comments received concerning the Preliminary Work Plan (PWP) in the Summary Document 

which was posted in the chlorhexidine derivatives registration review docket, and any other 

comments concerning the initial docket postings. The Summary Document provided information 

on what EPA knows about the pesticide and what additional risk analyses and data or 

information the Agency believes are needed to make a registration review decision.

Introduction

The Agency is implementing the registration review program pursuant to Section 3(g) of the 

Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and will review each registered 

pesticide every 15 years to determine whether it continues to meet the FIFRA standard for 

registration. Changes in science, public policy and pesticide use practices will occur over time. 

The registration review program is intended to make sure that, as the ability to assess risk 

evolves and as policies and practices change, all registered pesticides continue to meet that 

statutory standard. The public phase of registration review begins when the initial docket is 

opened for each case. Information on this program is provided at: 

http://www.epa.gov/oppsrrd1/registration_review/.

The Chlorhexidine Derivatives Case (Case Number 3038) includes three active ingredients, 

chlorhexidine diactetate (PC Code 045502), chlorhexidine digluconate (PC Code 045504) and 

chlorhexidine dihydrochloride (PC Code 481700). When EPA created the schedule for 

evaluating chemicals under the registration review program, chlorhexidine dihydrochloride (PC 

Code 481700) was identified as being part of the chlorhexidine derivatives registration review 

case. After further review, the Agency has determined that there are no registered pesticide 

products containing chlorhexidine dihydrochloride as an active ingredient (AI) and, thus, 

chlorhexidine dihydrochloride is not subject to evaluation under registration review and will be 

removed from Case 3038.

Chlorhexidine diacetate is registered for use as hard surface-treatment disinfectants, sanitizers, 

bactericides and virucides. Chlorhexidine diacetate is also registered to control bacteria in 

agricultural premises and equipment and to control certain viruses in animal premises and 

equipment, egg handling and packing equipment, and meat processing plants. Chlorhexidine 

digluconate is registered for use as a disinfectant for hard, non-porous surfaces (wheelchairs, 

metal bed frames, exteriors of toilets, countertops, metal surfaces, imaging equipment surfaces, 

glass, acrylic, and porcelain) in hospitals, restrooms, schools, offices, gyms, and homes. 

Chlorhexidine digluconate is also registered for use to control microbial contamination in dental 

unit waterlines. There are no tolerances or exemptions from requirements of a tolerance 

established for either chlorhexidine diacetate or chlorhexidine digluconate used as a pesticide.

The first products containing chlorhexidine diacetate and chlorhexidine digluconate as active 

ingredients were registered in the United States in 1955 and 1987, respectively. A reregistration 

eligibility decision (RED) for chlorhexidine diacetate was completed in 1996. Chlorhexidine 

digluconate was first registered after November 1, 1984, and; therefore, was not subject to the 

reregistration program. Currently, there are four chlorhexidine diacetate and one chlorhexidine 
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diglucaonate products registered with EPA. The Chlorhexidine Derivatives Preliminary Work 

Plan (PWP) was published on March 30, 2011 and the 60-day comment period ended on May 31, 

2011. Documents associated with the registration review of chlorhexidine derivatives can be 

viewed at www.regulations.gov in docket EPA-HQ-OPP-2011-0069.

EPA received one comment during the public comment period on the initial docket, described 

below. In the PWP, EPA also solicited comments on three specific topics: environmental 

justice; water body impairment; and trade irritants. No comments or information were received 

during the public comment period concerning these issues. 

Comments Received on the Preliminary Work Plan

Comment: The FIFRA Endangered Species Task Force (FESTF) submitted a comment 

requesting that the lead technical registrants for chlorhexidine derivates, Fort Dodge 

Animal Health and Procter & Gamble Company, who are not a members of the FESTF 

(or a company having met its data compensation obligations), provide a formal offer-topay to FESTF for reliance on their data or be required to develop substantially similar 

data on their own. 

Response: The Agency thanks FESTF for its comment and will consider this information 

as it conducts the registration review and makes its registration review decisions for 

chlorhexidine derivates.

The comment received during the initial public comment period did not affect the data needs, 

work plan and timeline described in the PWP and they remain as they were presented initially in 

the PWP. Further, this document makes final the work plan for the chlorhexidine derivates 

registration review process.

The Agency will conduct a comprehensive ecological risk assessment, including an endangered 

species risk assessment, for all uses of chlorhexidine derivatives. The Agency will also conduct a

human health risk assessment. The Agency will require additional data for use in conducting the 

registration review for chlorhexidine derivatives.

Risk Assessments and Anticipated Data Needs

Ecological Risk Assessment Status and Data Needs

• Based on ecotoxicity studies submitted to the Agency, chlorhexidine diacetate was found to 

be slightly toxic to practically nontoxic to avian species, moderately toxic to cold water fish, 

and highly toxic to warm water fish and aquatic invertebrates. Chlorhexidine digluconate is 

slightly toxic to avian species and highly toxic to cold water fish, warm water fish and 

aquatic invertebrates.

• An environmental fate assessment has not been completed due to the lack of data on the 

chlorhexidine derivatives.
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• The Agency has not conducted a risk assessment that supports a complete endangered 

species determination for chlorhexidine derivatives. The ecological risk assessment planned 

during registration review will allow the Agency to determine whether chlorhexidine 

derivatives’ uses have 'no effect' or 'may affect' federally listed threatened or endangered 

species (listed species) or their designated critical habitats. When an assessment concludes 

that a pesticide’s use 'may affect' a listed species or its designated critical habitat, the Agency 

will consult with the U.S. Fish and Wildlife Service and/or National Marine Fisheries 

Services (the Services), as appropriate.

• The Agency anticipates conducting ecological risk and environmental fate assessment for the 

registration review of chlorhexidine derivatives based on use in disinfectant/sanitizers used in 

animal premises and dental unit water lines that may potentially pass through waste water 

treatment plants and be discharged into terrestrial and aquatic environments. 

• The Agency anticipates the need to require the following additional ecological data for use in 

conducting the registration review of chlorhexidine derivatives.

850.5400 -- Algal Toxicity (Tier II) Using Freshwater Green Alga, Selenastrum 

capricornutum 

• The Agency anticipates the need to require the following additional environmental fate data 

for use in conducting the registration review of chlorhexidine derivatives.

835.2120 -- Hydrolysis

835.2240 -- Photodegradation in water

850.6800 -- Modified activated sludge, respiration inhibition test

835.1110 -- Activated Sludge Sorption Isotherm

835.3110 -- Ready Biodegradability

• For more information, please refer to Summary of Product Chemistry, Environmental Fate, 

and Ecotoxicity Data for the Chlorhexidine Derivatives Registration Review Decision 

Document, located in the docket.

Human Health Risk Assessment Status and Data Needs

• The most recent human health risk assessment for chlorhexidine diacetate was conducted in 

support of the 1996 RED. The most recent human health risk assessment for chlorhexidine 

digluconate was completed in 2010 in support of its use in dental unit waterlines. 

• The Agency has identified one product that is registered "for dipping teats as an aid in 

controlling bacteria that causes mastitis." EPA will examine this use as part of the 

registration review process.

• A dietary risk assessment was not conducted for the 1996 RED because at that time, the U.S. 

Department of Agriculture and the EPA agreed that disinfectants, when applied to federally 

Dietary Assessment
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inspected meat, poultry, egg, and rabbit processing plants, did not present dietary exposure 

risks (USDA, FSIS publication# 1419, “List of Proprietary Substances and Nonfood 

Compounds”). This publication was no longer updated after 1998 and this policy is now 

referred to as a “former” guideline or “former requirement;” therefore, the Agency 

anticipates conducting a dietary risk assessment for the registration review of chlorhexidine 

derivatives.

• There are no tolerances or exemptions from requirements of a tolerance established for either 

chlorhexidine diacetate or chlorhexidine digluconate used as a pesticide.

Tolerances and International Harmonization

• An occupational risk assessment was conducted for chlorhexidine diacetate in the 1996 RED 

based on potential exposures from its use as a non-porous, hard surface disinfectant in 

various agricultural and veterinary settings. Risks exceeded EPA’s level of concern for the 

wet mist fogging use scenario assessed in the Chlorhexidine Diacetate RED. This 

exceedance was addressed by label language requiring ventilation prior to re-entry into the 

treated area. The Agency determined all registered uses of chlorhexidine diacetate were 

eligible for reregistration. 

Occupational and Residential Assessment and Risk

• The most recent human health risk assessment for chlorhexidine digluconate was conducted 

in 2010. Due to the small amount of product used per treatment, the high dilution of the 

active ingredient in the product, and the method of application, the Agency determined that 

the occupational exposures would be minimal in comparison to the toxicology endpoints; 

therefore, an occupational risk assessment was not completed.

• A residential risk assessment has not been conducted for chlorhexidine derivatives. 

• The Agency anticipates conducting residential and occupational exposure risk assessments 

for the registration review of chlorhexidine derivatives based on current use patterns.

• The Agency has not previously conducted an aggregate risk assessment for chlorhexidine 

derivatives.

Aggregate and Cumulative Exposure and Risk

• The Agency anticipates conducting an aggregate risk assessment for the registration review 

of chlorhexidine derivatives. 

• EPA does not have, at this time, available data to determine whether chlorhexidine 

derivatives have a common mechanism of toxicity with other substances or how to include 

this pesticide in a cumulative risk assessment. For the purposes of this Registration Review, 

EPA has assumed that chlorhexidine derivatives do not have a common mechanism of 

toxicity with other substances when used as an antimicrobial as registered. 
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• The Agency anticipates the need to require the following additional human health data to 

conduct the registration review of chlorhexidine derivatives.

Human Health Data Needs

870.3465 -- 90-day inhalation toxicity (rat)

870.5100 -- Bacterial reverse mutation assay

870.5395 -- Mammalian erthrocyte micronucleus test

875.1200 -- Dermal indoor exposure

875.1400 -- Inhalation indoor exposure

875.1600 -- Application exposure data reporting and calculations

875.1700 -- Product use information

875.2300 -- Indoor surface residue dissipation

• For more information, please refer to Chlorhexidine Derivatives (Chlorhexidine 

Diacetate and Chlorhexidine Digluconate): Human Health Assessment Scoping 

Document in Support of Registration Review, located in the docket.

Product Chemistry:

• The Agency does not anticipate the need to require additional product chemistry data for

this registration review at this time.

• For more information, please refer to Summary of Product Chemistry, Environmental 

Fate, and Ecotoxicity Data for the Chlorhexidine Derivatives Registration Review 

Decision Document, located in the docket.

Ecological:

Incidents

• There were seven animal incidents associated with chlorhexidine exposure reported in the 

OPP Incident Data System (IDS). There were seven domestic animal incidents reported 

involving cats and dogs exposure to chlorhexidine diacetate from pesticidal uses. For 

cats, the symptoms following exposure to a chlorhexidine diacetate solution were skin 

redness, inflammation at the site of exposure, weakness, central nerve system signs, 

apnea, respiratory arrest, comatose-like state and death. For dogs, the symptoms after 

chlorhexidine exposure were facial paralysis and deafness.

Human Health:

• There were three human incidents associated with chlorhexidine exposure reported in the 

OPP Incident Data System (IDS). The three human incidents reported to be associated 

with chlorhexidine exposure from pesticidal uses included: (1) tracheal edema in a 

woman following her visit to a veterinarian’s office where a chlorhexidine solution had 

been used, (2) severe cold-like symptoms that progressed to bronchitis in a woman 

running a cattery housing six cats who used a chlorhexidine solution to disinfect cages, 
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and (3) dermal sensitization symptoms occurring in one person after dermal exposure to a 

chlorhexidine cleaning solution.

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 the 1996 chlorhexidine diacetate reregistration decision and the 

2010 chlorhexidine digluconate registration, 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), chlorhexidine derivatives are subject to the 

endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 

Endocrine Disruptor Screening Program

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. Chlorhexidine 

derivatives were 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 chlorhexidine 

derivatives. 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/.
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Timeline

EPA has created the following estimated timeline for the completion of the chlorhexidine 

derivatives registration review:

Anticipated Schedule

Activities Estimated Month/Year

Phase 1: Opening the docket

Open Public Comment Period for Docket Completed

March 2011

Close Public Comment Period for Docket Completed

May 2011

Phase 2: Case Development

Develop Final Work Plan (FWP) Completed

September 2011

Issue DCI September 2012

Data Submission September 2014

Open Public Comment Period for Preliminary Risk Assessments March 2016

Close Public Comment Period for Preliminary Risk Assessments June 2016

Phase 3: Registration Review Decision

Open Public Comment Period for Proposed Reg. Review Decision September 2017

Close Public Comment Period for Proposed Reg. Review Decision December 2017

Final Decision and Begin Post-Decision Follow-up March 2017

Total (years) 6

Next Steps

A DCI will be developed regarding the data needs listed under the “Risk Assessments and Data 

Needs” section of this document. The Agency anticipates issuing the DCI in September 2012 and 

conducting human health, environmental fate and ecological risk assessments for all uses. 
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Summary of Anticipated Data Requirements – Chlorhexidine Derivatives

The table below summarizes anticipated data needs for the Chlorhexidine Derivatives Case.

Table 1. Summary of Anticipated Data Requirements – Chlorhexidine Derivatives

Active 

Ingredient

Guideline 

Number

Anticipated Data Requirement Test 

Material

Estimated 

Timeframe

(Measured 

in Months

from DCI 

Receipt)

045502 or 

045504 835.2120 Hydrolysis TGAI 12

045502 or 

045504 835.2240 Photodegradation in water TGAI 12

045502 or 

045504 850.6800 Modified Activated Sludge Respiration Inhibition TGAI 12

045502 or 

045504 835.1110 Activated Sludge Sorption Isotherm TGAI 12

045502 or 

045504 835.3110 Ready Biodegradability TGAI 12

045502 or 

045504 850.5400 Aquatic growth, Tier II green algae TGAI 12

045502 or 

045504 870.3465 90-day Inhalation Toxicity TGAI 24

045502 or 

045504 870.5100 Bacterial Reverse Mutation Test TGAI 8

045502 or 

045504 870.5395 Mammalian Erythrocyte Micronucleus Test TGAI 8

045502 and 

045504 875.1200 Dermal Exposure - Indoor TGAI 24

045502 and 

045504 875.1400 Inhalation Exposure - Indoor TGAI 24

045502 and 

045504 875.1600 Data Reporting and Calculations TGAI 24

045502 and 

045504 875.1700 Product Use Information TGAI 12

045502 or

045504 875.2300 Indoor surface residue dissipation TGAI/TEP 24