4-CP A Human Health Risk Assessment DP No. D419151 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: 07/17/2014 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: 4-Chlorophenoxyacetic acid. Human Health Risk Assessment in Support of 

Registration Review. 

PC Code: 01940 I 

Decision No.: 489496 

Petition No.: NA 

DP Barcode: 0419151 

Registration No.: NA 

Regulatory Action: Registration Review 

Risk Assessment Type: Single Chemical Case No.: NA 

TXRNo.: NA CAS No.: 122-88-3 

MRIDNo.: NA 40 CFR: 180.202 

FROM: Ideli

Ana Rivera-Lupiaiiez 

z Negron-Encarnacion, 

I Seyed 

Ph.D., 

Tadayon, 

Risk 

Chemists 

Assesso ' ' ~ 

j c..J2 _ 

~ 

. _ J 

Ronnie J. Bever, Jr., Ph.D., Toxicologist · 'I ~ 't1 

Risk Assessment Branch (RAB) VNII 

Health Effects Division (HED; 7509P 

THROUGH: William Irwin, Ph.D., DABT, Toxi~o 

MichaelS. Metzger, Branch Chief 

RAB V/VII (HED; 7509P) 

TO: Miguel A. Zavala, Chemical Review Manager 

Patricia Parrott, Branch Chief 

Risk Management and Implementation Branch III 

Pesticide Re-evaluation Division (7508P) 

Page 1 of32 
4-CPA Human Health Risk Assessment DPNo. 0419151 

1.0 Executive Summary ......................................................................................................... 3 

2.0 HED Recommendations .................................................................................................. 4 

2.1 Data Deficiencies .............................................................................................................. 4 

2.2 Tolerance Considerations and International Harmonization ..................................... 4 

2.3 Label Recommendations ................................................................................................. 4 

3.0 Introduction ..................................................................................................................... 4 

3.1 Chemical Identity ......................................................•..................................................... 4 

3.2 Physical/Chemical Characteristics ................................................................................. 5 

3.3 Pesticide Use Pattern ....................................................................................................... 5 

3.4 Anticipated Exposure Pathways ..................................................................................... 5 

3.5 Consideration of Environmental Justice ....................................................................... 6 

4.0 Hazard Characterization and Dose-Response Assessment ............•............................. 6 

4.1 Summary of Toxicological Effects .................................................................................. 6 

4.2 Safety Factor for Infants and Children (FQPA Safety Factor) .....•............................. 8 

4.2.1 Completeness of the Toxicology Database .......................................•............................. 8 

4.2.2 Evidence of Neurotoxicity ............................................................................................... 8 

4.2.3 Evidence of Sensitivity /Susceptibility in the Developing or Young Animal. .............. 8 

4.2.4 Residual Uncertainty in the Exposure Database .......................................................... 8 

4.3 Toxicity Endpoint and Point of Departure Selections ....................•............................. 9 

5.0 Dietary Exposure and Risk Assessment ...................................................................... 11 

5.2 Food Residue Profile ..................................................................................................... 11 

5.3 Water Residue Profile ................................................................................................... 11 

5.4 Dietal)' Risk Assessment ............................................................................................... 11 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ........................... 12 

6.1 Residential Handler and Post-Application Exposure ................................................. 12 

6.2 Spray Drift and By-Stander Exposure ........................................................................ 12 

7.0 Aggregate Exposure/Risk Characterization ............................................................... 12 

8.0 Cumulative Exposure/Risk Characterization ............................................................. 13 

9.0 Occupational Exposure/Risk Characterization .......................................................... 13 

10.0 Public Health and Pesticide Epidemiology Data ........................................................ 16 

Appendix A. Toxicology Profile and Executive Summaries .................................................. 17 

A.1 Toxicology Data Requirements .........................................................•.......................... 17 

A.2 Toxicity Profiles ............................................................................................................. 18 

Appendix B: Toxicity Studies with 4-chlorophenoxyacetic acid (4-CPA) and Structures 

Related to 4-CP A ......................................................................................................................... 22 

Appendix C. Physical/Chemical Properties ..................................................•.......................... 30 

Appendix D. Chronic Dietary Assessment for 4-Chlorophenoxyacetic Acid ....................... 31 

Appendix E. International Residue Limits ...................................................•.......................... 32 

Page 2 of 32 
4-CPA Human Health Risk Assessment DP No. D419151

Page 3 of 32

1.0 Executive Summary

The HED Registration Review Team has prepared a preliminary human health risk assessment to 

support registration review for the uses of 4-chlorophenoxyacetic acid (4-CPA). In addition, as 

the scoping phase was performed in conjunction with the risk assessment, HED has considered 

updates to the toxicity, exposure, and usage databases. Current Agency science policy and risk 

assessment methodologies were employed. In addition, HED conducted an open literature 

search to look for new literature relevant to the human health risk assessment. The results of the 

literature search showed that no new information relevant to the human health risk assessment 

has been published. When writing this risk assessment, HED primarily considered the following 

two documents: The HED Chapter of the Reregistration Eligibility Decision (RED) for 4-CPA 

(Mary R.A. Clock; 12/22/1994); The Reregistration Eligibility Decision for 4-CPA (March 

1997); and The HED Chapter for the Tolerance Reregistration Eligibility Decision (TRED) (C. 

Christensen, 3/12/2003, D288835).

4-CPA is currently registered for use as a root suppression agent for mung bean sprouts. 4-CPA 

is formulated in end-use products as a dry amorphous powder. It is dissolved in boiling water 

and applied by direct pour or by closed delivery systems to a water bath to soak the beans.

Tolerances are established in the 40 CFR §180.202 for residues of 4-CPA in/on bean, mung, 

sprouts at 0.2 ppm. Residue chemistry deficiencies were not identified in the 2003 TRED and 

new uses have not been registered since then. The tolerance expression needs to be modified to 

exclude measurement of the metabolite, 4-chlorophenol, and include the language recommended 

in the new Interim Guidance on Tolerance Expressions. 

Chronic dietary assessment (food only) was conducted. Risk estimates were below HED’s level 

of concern for the general population and for all population subgroups. 

There are currently no registered residential uses for 4-CPA. The registered uses for 4-CPA are 

not expected to result in residential exposure; therefore, a quantitative residential exposure 

assessment has not been conducted. In addition, due to the limited use in indoor facilities, bystander exposure and spray drift are not likely. 

Since there are no residential uses and drinking water exposure is not expected, the aggregate 

exposure and risk includes food only. Food-only risks are not of concern.

HED conducted a quantitative occupational exposure and risk assessment. The occupational 

handler exposure and risk assessment indicates that the risk estimates (i.e., the margins of 

exposures; MOEs) are below the Agency’s Level of Concern (i.e., MOEs > LOC of 100). There 

is a potential for post-application exposure for workers but is expected to be lower than that of 

applicators. 
4-CPA Human Health Risk Assessment DP No. D419151

Page 4 of 32

2.0 HED Recommendations

2.1 Data Deficiencies

None. 

2.2 Tolerance Considerations and International Harmonization

A tolerance of 0.2 ppm is established in the 40 CFR §180.202 for residues of 4-CPA in/on bean, 

mung, sprouts. The tolerance expression includes measurement of residues of 4-

chlorophenoxyacetic acid and it metabolite 4-chlorophenol in/on mung beans. The RED (March 

1997) and HED Chapter for the RED (W. Smith, D198945, 10/14/1994) recommended approval 

of a registrant petition for the elimination of the metabolite 4-chlorophenol from the tolerance 

expression as it was not considered a metabolite of risk concern. The tolerance expression needs 

to be updated to reflect this change.

HED established interim guidance on writing tolerance expressions for enforcement purposes (S. 

Knizner, 27/May/2009). In order to add clarity to the language used to establish the coverage of 

the tolerance expression and measurement of the level of the residue in the Raw Agricultural 

Commodity (RAC) the text in the 40 CFR § 180.202 should read: “(a) General. (1) Tolerances 

are established for residues of p-chlorophenoxyacetic acid, including its metabolites and 

degradates, in or on the commodities in the table below. Compliance with the tolerance levels 

specified below is to be determined by measuring p-chlorophenoxyacetic acid in or on the 

commodity.”

Where possible, EPA encourages the harmonization of the US Tolerances and Maximum 

Residue Limits (MRLs) in key export markets. A table with the US tolerances, the Canada 

MRLs, Mexico MRLs and Codex MRLs for 4-CPA in mung beans is provided in Appendix E -

International Residue Limits. There are currently no established Codex and Mexican MRLs for 

4-CPA in/on mung beans. Canada has a MRL of 2 ppm for residues of 4-chlorophenoxyacetic 

acid in/on mung beans. Based on communication with Canada the data submitted to the USA 

that resulted in the current tolerance has not been submitted to them. 

Conclusions: The residue chemistry database is adequate to support uses in mung beans. The 

tolerance expression needs to be modified to exclude measurement of the metabolite 

4-chlorophenol, and to reflect the language recommended in the interim guidance for writing 

tolerance expressions.

2.3 Label Recommendations

None.

3.0 Introduction

3.1 Chemical Identity
4-CPA Human Health Risk Assessment DP No. D419151

Page 5 of 32

Table 3.1 Test Compound Nomenclature

Chemical Structure

Empirical Formula C9H9ClO3

IUPAC name 2-(4-chloro-2-methylphenoxy)acetic acid

CAS Name 4-Chlorophenoxyacetic acid

CAS Registry Number 122-88-3

End-use product/EP Amorphous powder

Chemical Class Chlorophenoxy1

1 Pesticides in this class are herbicides but 4-CPA is used as a plant growth regulator.

3.2 Physical/Chemical Characteristics

4-CPA is highly soluble in water (957 mg/L) and has an estimated vapor pressure of 3.2x10-4 mm 

Hg at 25 deg C. Based on 4-CPA pKa of 3.56, it will ionize in water at neutral and basic pHs 

resulting in the formation of 4-chlorophenoxyacetate which is not expected to volatilize. Refer to 

Appendix C for the physicochemical properties of 4-CPA.

3.3 Pesticide Use Pattern

The use pattern has not changed since December 1999. The chemical 4-CPA is used in the food 

industry as a plant growth regulator to restrict root growth during seed germination of mung 

beans. The end-use product is limited to indoor use. The active ingredient 4-CPA is formulated 

in end-use products as a dry amorphous powder (96.2% ai). It is dissolved in boiling water and 

the solution applied by direct pour or by closed delivery to the water bath where the beans are 

soaked, resulting in a concentration of 2-3 ppm of 4-CPA. After the beans have soaked for 6-8

hours, they are washed to remove the surface residues, and are then germinated indoors for 

several days. After sprouting, the hulls and roots are discarded, and the remaining portion is 

packaged and sold for human consumption. 

Conclusions: According to information provided by the registrant, the average annual use of 

4CPA in the USA is 20 pounds active ingredient per year (M. Clayton, PRD minutes of first 

team meeting 02/18/2014). Current uses of 4-CPA include mung bean only. If, in the future, the 

use profile changes additional data may be required.

3.4 Anticipated Exposure Pathways

The Pesticide Reevaluation Division has requested an assessment of human health risk to support 

the registration review risk assessment of 4-CPA. Humans may be exposed to 4-CPA in food, 

since 4-CPA is applied directly to beans before germination. Application is indoors and the use 

is limited; therefore, 4-CPA is not likely to reach surface and ground water sources of drinking 

water. There are no residential uses of 4-CPA, so there is not likely to be exposure in residential 
4-CPA Human Health Risk Assessment DP No. D419151

Page 6 of 32

or non-occupational settings. In an occupational setting, applicators may be exposed while 

handling the pesticide prior to application, as well as during application. There is a potential for 

post-application exposure for workers but is expected to be lower than that of applicators. 

Risk assessments have been previously conducted for 4-CPA, but no new toxicity data have been 

received since the previous risk assessment. A detailed description of the toxicity data and 

metabolism information may be found in the risk assessment dated 3/12/2003 (C. Christensen, 

D288835). This risk assessment considers all of the aforementioned exposure pathways based 

on the registered use of 4-CPA. 

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA under the National 

Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and 

are used in pesticide risk assessments for all registered food uses of a pesticide. These data are 

analyzed and categorized by subgroups based on age, season of the year, ethnic group, and 

region of the country. Additionally, OPP is able to assess dietary exposure to smaller, 

specialized subgroups and exposure assessments are performed when conditions or 

circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of 

pesticide products and associated risks for adult applicators and for toddlers, youths, and adults 

entering or playing on treated areas post-application are evaluated. Further considerations are 

currently in development as OPP has committed resources and expertise to the development of 

specialized software and models that consider exposure to bystanders and farm workers as well 

as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Summary of Toxicological Effects

The mode of action in plants for 4-CPA is growth regulation (auxin), but the mode of action for 

toxicity in animals is unknown.

The toxicology database for 4-CPA is adequate for risk assessment. Acceptable, guideline 

studies for the subchronic oral toxicity in rats, developmental in rats, and mutation battery 

were submitted. These studies are briefly described below. All other toxicity study 

requirements have been waived (see the Hazard and Science Policy Council (HASPOC; 

5/28/2014). See Appendix A for the Toxicological Profile of 4-CPA. Other structural analogs 
4-CPA Human Health Risk Assessment DP No. D419151

Page 7 of 32

of 4-CPA were reviewed to better characterize the toxicity of 4-CPA. In that review, 4-CPA

was among the least toxic of the analogues, See Appendix B. 

In a subchronic toxicity study with rats, the NOAEL was 132 mg/kg/day, and the LOAEL was 

517 mg/kg/day based on decreased body weight in both sexes, decreased food consumption in

females, increased urine volume in females, and increased incidence of slight hepatic

lymphohistiocytic infiltrates and slight individual hepatocellular necrosis. 

In a subchronic toxicity study with dogs, the NOAEL was 17.4 mg/kg/day (500 ppm), the

highest dose tested. Transient effects in the dog study included decreased body weight gain and

food consumption during the first four weeks at the highest dose (which may have been related

to palatability) and slightly higher incidence of vomiting. Malnutrition was noted at 1600 and

3200 ppm in a range-finding study in dogs.

In a developmental toxicity study in rats, maternal toxicity was observed at a LOAEL of 1000 

mg/kg/day including mortality, and clinical signs of neurotoxicity: tremors, uncoordinated

movements, recumbent posture, languidness, cold body, and yellow staining in the anogenital 

area. The NOAEL was 600 mg/kg/day. The developmental LOAEL of 600 mg/kg/day was 

based on decreased fetal body weights and unossified sternebrae. The NOAEL was 300 

mg/kg/day. Thus, increased susceptibility was noted in the offspring compared to the 

adults.

4-CPA tested in an in vitro mammalian mutation assay did not induce forward mutations in 

mouse lymphoma cells. In the Ames Salmonella/mammalian-microsomal reverse mutation 

assay, 4-CPA was not mutagenic, with or without activation. This chemical was not clastogenic 

in an in vivo mouse micronucleus assay. Due to the lack of chronic toxicity and carcinogenicity 

studies, a number of structurally similar chemical compounds were evaluated to better 

characterize the hazard potential of 4-CPA. Only 1 out of 16 mutagenicity studies available for 

the structural analogs was positive for mutation. See Appendix B.

The Office of Pollution and Prevention and Toxics (OPPT) Structural Activity Relationship 

(SAT) workgroup evaluated 4-CPA and its associated analogues for carcinogenic potential. The 

workgroup concluded that there is a low, marginal concern for the carcinogenicity of this 

compound.

Chlorophenoxy compounds are well absorbed from the gastrointestinal tract. They are less well 

absorbed from the lung. Cutaneous absorption appears to be minimal. The compounds are not 

significantly stored in fat. Excretion occurs almost entirely by way of urine, and the excretion 

process is saturable. Apart from some conjugation of the acids, there is limited

biotransformation in the body. The compounds are highly protein bound. Also, it is known that 

the chemicals 2,4-D and 4-CPA have substantially similar metabolism patterns. Specifically, the 

dog is not able to excrete the phenoxy acids as rapidly as the rat.
4-CPA Human Health Risk Assessment DP No. D419151

Page 8 of 32

4.2 Safety Factor for Infants and Children (FQPA Safety Factor)

The FQPA Safety Factor was removed (i.e., 1X), since: developmental toxicity in rats 

manifested only at a relatively high dose (600 mg/kg/day); there is limited dietary exposure;

there is no exposure to infants and children resulting from residential uses; and the chronic 

reference dose will be protective of the developmental concerns and neurotoxic effects.

4.2.1 Completeness of the Toxicology Database

The toxicology database is considered adequate for risk assessment. In 1997, the Agency granted 

waivers for the chronic toxicity, carcinogenicity and reproductive toxicity due to the lack of 

overt toxicity in subchronic dietary studies, the low volume/minor use status and the lack of 

acute dietary exposure concerns of 4-CPA (EPA738 R-97-001). 

On April 24, 2014, HED’s Hazard Science Policy Council (HASPOC) concurred with the 

waivers for the long-term studies and further granted waivers to the neuro-, dermal-, inhalation, 

and immunotoxicity studies using a weight of evidence approach considering all of the available 

4-CPA hazard and exposure information. Using tolerance level residue values for mung bean, 

and assuming 100% of crop treated, the chronic dietary risk was <1% of the cPAD for the 

general population and all population subgroups. An assessment of occupational handler showed 

that risk estimates are not of concern (i.e., dermal MOE = 95,000 and inhalation MOE = 

8,148,000). Similarly, a screening level of occupational handler inhalation exposure and risk 

considering this value resulted in an MOE of 170,000 at label PPE (TXR No.0056953).

4.2.2 Evidence of Neurotoxicity

The tremors, uncoordinated movements, recumbent posture, languidness, and cold body noted in 

mothers in a developmental toxicity study in rats were seen only at the Limit Dose (1000 

mg/kg/day). No clinical signs of neurotoxicity were seen in the subchronic toxicity studies in 

rats and dogs. 

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There was evidence for increased susceptibility in the developmental toxicity study in rat where 

developmental toxicity (decreased fetal body weights and unossified sternebrae) was observed in 

the absence of maternal toxicity. However, there is low concern for the observed effects since 

they occurred at 600 mg/kg/day which is higher than one-half of the Limit Dose and the chronic 

RfD would be protective of these effects. 

4.2.4 Residual Uncertainty in the Exposure Database

There are no uses of 4-CPA in the residential environment, and dietary exposure to the chemical 

will not be underestimated. 
4-CPA Human Health Risk Assessment DP No. D419151

Page 9 of 32

4.3 Toxicity Endpoint and Point of Departure Selections

The NOAEL from the rat subchronic toxicity study was selected as the Point of Departure for the 

chronic dietary and occupational risk assessments. There are no residential uses for this 

chemical; therefore, no endpoints were identified for these exposure scenarios. Additionally, 

HED has determined that post-application exposure will be minimal, and no quantitative risk 

assessment for such exposure is necessary.

Table 4.3.1 Summary of Toxicological Doses and Endpoints for 4-CPA for Use in Dietary Human Health 

Risk Assessments a

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/FQP

A Safety Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(General 

Population, 

including 

Infants and 

Children)

No effect was identified from the supplied studies.

Acute Dietary

(Females 13-

49 years of 

age)

No effect was identified from the supplied studies.

Chronic 

Dietary (All 

Populations)

NOAEL= 

132

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF= 1x

Chronic RfD 

= 1.32

mg/kg/day

cPAD = 1.32

mg/kg/day

MRID 42968301: 90-day oral toxicity

study in rat

NOAEL = 132/153 mg/kg/day in males 

and females, respectively.

LOAEL = 517/626 mg/kg/day in males 

and females, respectively, based on 

decreased body weights in males and 

females and lymphohistiocytic 

infiltration and individual hepatocyte 

necrosis in males and increased urine 

volume in females.

Cancer (oral, 

dermal, 

inhalation)

Classification: Not evaluated. Waivers were granted for the carcinogenicity studies.

1 There are no residential uses of 4-CPA.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c 

= chronic). RfD = reference dose. N/A = not applicable.
4-CPA Human Health Risk Assessment DP No. D419151

Page 10 of 32

Table 4.3.2 Summary of Toxicological Doses and Endpoints for 4-CPA for Use in Occupational Human 

Health Risk Assessments a

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal ShortTerm (1-30 

days)

NOAEL =

132

mg/kg/day

UFA=10x

UFH=10x

Occupational 

LOC for MOE = 

100

MRID 42968301: 90-day oral toxicity 

study in rat

NOAEL = 132/153 mg/kg/day in males 

and females, respectively.

LOAEL = 517/626 mg/kg/day in males 

and females, respectively, based on 

decreased body weights in males and 

females and lymphohistiocytic infiltration 

and individual hepatocyte necrosis in 

males and increased urine volume in 

females.

Dermal 

IntermediateTerm (1-6 

months)

NOAEL =

132

mg/kg/day

UFA=10x

UFH=10x

Occupational 

LOC for MOE = 

100

MRID 42968301: 90-day oral toxicity 

study in rat

NOAEL = 132/153 mg/kg/day in males 

and females, respectively.

LOAEL = 517/626 mg/kg/day in males 

and females, respectively, based on 

decreased body weights in males and 

females and lymphohistiocytic infiltration 

and individual hepatocyte necrosis in 

males and increased urine volume in 

females.

Inhalation 

Short-Term 

(1-30 days)

NOAEL =

132

mg/kg/day

UFA=10x

UFH=10x

Occupational 

LOC for MOE = 

100

MRID 42968301: 90-day oral toxicity 

study in rat

NOAEL = 132/153 mg/kg/day in males 

and females, respectively.

LOAEL = 517/626 mg/kg/day in males 

and females, respectively, based on 

decreased body weights in males and 

females and lymphohistiocytic infiltration 

and individual hepatocyte necrosis in 

males and increased urine volume in 

females.

Inhalation 

Intermediateterm (1-6 

months)

NOAEL =

132

mg/kg/day

UFA=10x

UFH=10x

Occupational 

LOC for MOE = 

100

MRID 42968301: 90-day oral toxicity 

study in rat

NOAEL = 132/153 mg/kg/day in males 

and females, respectively.

LOAEL = 517/626 mg/kg/day in males 

and females, respectively, based on 

decreased body weights in males and 

females and lymphohistiocytic infiltration 

and individual hepatocyte necrosis in 

males and increased urine volume in 

females.

Cancer (oral, 

dermal, 

inhalation)

Classification: Not evaluated. Waivers were granted for the carcinogenicity studies.

a The dermal and inhalation absorption factors are very conservatively assumed to be 100%. No study was 

presented to establish the absorption factors. 
4-CPA Human Health Risk Assessment DP No. D419151

Page 11 of 32

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

5.0 Dietary Exposure and Risk Assessment 

5.2 Food Residue Profile

The metabolism of 4-CPA is adequately understood in plants and in animal commodities based 

upon previously submitted and reviewed plant and animal metabolism studies. Currently, the 

only use registered is in mung beans for which a tolerance of 0.2 ppm has been established. In 

addition, residue analytical methods, storage stability, magnitude of the residue in plants, 

processed food/feed, and in meat, milk, poultry and eggs, and confined field rotation studies are 

either acceptable or not required, based upon the use pattern. See the March 1997 RED for more 

detail. 

5.3 Water Residue Profile

No exposure from drinking water is expected due to the limited indoor use of 4-CPA. 

5.4 Dietary Risk Assessment

Chronic aggregate dietary (food only) exposure and risk assessments was conducted using the 

Dietary Exposure Evaluation Model software with the Food Commodity Intake Database 

(DEEM-FCID) Version 3.16. This software uses 2003-2008 food consumption data from the 

U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, 

What We Eat in America, (NHANES/WWEIA). The dietary exposure assessment utilized 

tolerance level residue values of 0.2 ppm for mung bean to assess the exposure to 4-CPA. The 

dietary exposure assessment included the chronic exposure scenario only with a chronic 

population adjustment dose (cPAD) of 1.32 mg/kg/day based on the NOAEL from the 

subchronic toxicity study in rats and uncertainty factors of 100 for intraspecies and interspecies 

differences. Using tolerance level residue values for mung bean, and assuming 100% of crop 

treated, the chronic dietary risk was < 1 % of the cPAD for the general population and all 

population subgroups. 
4-CPA Human Health Risk Assessment DP No. D419151

Page 12 of 32

Table 5.4.6. Summary of Dietary (Food Only) Exposure and Risk for 4-Chlorophenoxyacetic 

Acid

Population Subgroup

Acute Dietary

(XX.X Percentile) Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD*

Dietary 

Exposure

(mg/kg/day)

% cPAD*

Dietary 

Exposure

(mg/kg/day)

Risk

General U.S. Population

N/A

0.000000 < 1

All Infants (< 1 year old) 0.000000 < 1

N/A N/A

Children 1-2 years old 0.000000 < 1

Children 3-5 years old 0.000000 < 1

Children 6-12 years old 0.000000 < 1

Youth 13-19 years old 0.000001 < 1

Adults 20-49 years old 0.000001 < 1

Adults 50+ years old 0.000000 < 1

Females 13-49 years old 0.000000 < 1

*The values for the highest exposed population are bolded.

Conclusion: Dietary exposure assessment for 4-CPA showed risks below HED’s level of 

concern for the general population and all population subgroups.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

6.1 Residential Handler and Post-Application Exposure

A residential handler and post-application exposure assessment is not needed for Registration 

Review because there are no registered residential uses of 4-CPA. 

6.2 Spray Drift and By-Stander Exposure

The use of 4-CPA is limited to indoor uses; therefore, there is no need for spray drift and 

volatilization risk assessment as a result of applications of 4-CPA.

7.0 Aggregate Exposure/Risk Characterization

Since there are no residential uses and drinking water exposure is not expected, the aggregate 

exposure and risk includes food only. Food-only risks are not of concern.
4-CPA Human Health Risk Assessment DP No. D419151

Page 13 of 32

8.0 Cumulative Exposure/Risk Characterization

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 4-CPA and any other substances, and 4-CPA does not appear to produce a toxic metabolite 

produced by other substances. For the purposes of this tolerance action, therefore, EPA has not 

assumed that 4-CPA 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/.

9.0 Occupational Exposure/Risk Characterization

A quantitative occupational exposure risk assessment was not conducted during the 1997 

reregistration process due to the potentially low worker exposure associated with the growing of 

mung beans and the low mammalian toxicity profile of 4-CPA. However, at present, as part of 

the chemical’s registration review process, HED conducted a quantitative occupational exposure 

and risk assessment. There is potential for short- and intermediate-term occupational exposure to 

4-CPA during handling (mixing, loading, and applying) and post-application activities. 4-CPA is 

applied by direct pour or by closed delivery to the water bath to soak the beans. 

Occupational Handlers

The potential for worker exposure associated with growing mung beans is very low. However, 

4-CPA is a severe eye irritant and is classified as Toxicity Category I for eye irritation in 

mammalian species. Personal Protective Equipment (PPE) for handlers is based on the acute 

toxicity of the end- use product. The registered 4-CPA label requires occupational handlers to 

wear long-sleeved shirts, long pants, shoes, socks, and protective eyewear (goggles). 

An assessment of occupational handler exposure and risk was performed based on a value of 132

mg/kg/day. The NOAEL in the subchronic rat study was 132/153 mg/kg/day in males/females. 

Using the updated exposure methodology and current ORE policies indicates that occupational 

handler risk estimates are not of concern (i.e., dermal MOE =95,000 and inhalation MOE= 

8,148,000) at label PPE. See Table 9.1.

Furthermore, given the fact that the chemicals 2,4-D and 4-CPA are both members of the 

phenoxyacetic herbicide class of pesticides, and have substantially similar chemical structures 

and metabolism patterns, HED conducted an assessment of occupational handler inhalation 

exposure and risk utilizing the point of departure (PoD) of 2,4- D (i.e., Human Equivalent Dose 

(HED) of 2.68 mg/kg/day).1 A screening level of occupational handler inhalation exposure and 

risk considering this value resulted in an MOE of 170,000 at label PPE (i.e., without a 

respirator). This risk value estimate is very conservative and could be considered worse than a 

“worst case scenario”. Portal-of-entry effects have been a source of concern for 2,4-D and 

 

1 For details regarding the calculation of the Human Equivalent Dose, see D389455 (LaMay, A., 08/08/2013).
4-CPA Human Health Risk Assessment DP No. D419151

Page 14 of 32

MCPA (other chlorphenoxy compounds); however, HASPOC decided that an inhalation toxicity 

study was not needed for 4-CPA due to its low exposure and toxicity. See Table 9.2.

Occupational Post-Application

There is a possibility for workers to have post-application dermal exposure to 4-CPA following 

its uses. Occupational post-application exposure was not quantitatively assessed; however, based 

on 4-CPA’s use pattern and low exposure potential the occupational handler assessment is 

expected to be protective of potential worker post-application exposure. 

Conclusion: The occupational exposure database is complete for 4-CPA. No risks of concern 

were identified in the occupational handler and post-application assessments. 
4-CPA Human Health Risk Assessment DP No. D419151

Page 15 of 32

Table 9.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for 4-CPA.

Exposure 

Scenario Crop or Target

Inhalation Unit 

Exposure

(μg/lb ai)1

Dermal unit 

exposure 

(μg/lb ai)1

Maximum

Application 

Rate2

Area Treated 

Daily3

Inhalation Dermal

Combined 

MOE

Mitigation Level: Baseline

(No gloves, no respirator)

Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)4 MOE5

Mixer/Loader

Mixer/Loader, 

Wettable powder Mung Beans 43 3700

2.2E-05

lb ai/gallon 1,150 gallons 0.0000162 8,148,000 0.00139 95,000 95,000

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013); Level of mitigation: Baseline.

2 Based on 4-CPA Registered Label EPA Reg. No. 8906-1.

3 Based on 4-CPA Registered Label EPA Reg. No. 8906-1.

4 Dose = Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (gal/day) ÷ BW (kg).

5 MOE = NOAEL (132 mg/kg/day) ÷ Dose (mg/kg/day).

Table 9.2. Occupational Handler Non-Cancer Exposure and Risk Estimates for 4-CPA (using 2,4 D PoD).

Exposure Scenario Crop or Target

Inhalation Unit 

Exposure 

(μg/lb ai)1 Maximum

Application Rate2

Area Treated 

Daily3

Inhalation

Mitigation Level: 

No respirator Dose (mg/kg/day)4 MOE5

Mixer/Loader

Mixer/Loader, 

Wettable powder Mung Beans 43 2.2E-05 lb ai/gallon 1150 gallons 0.0000162 170,000

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013); Level of mitigation: Baseline.

2 Based on 4-CPA Registered Label EPA Reg. No. 8906-1.

3 Based on 4-CPA Registered Label EPA Reg. No. 8906-1.

4 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (gal/day) ÷ BW (kg).

5 Inhalation MOE = Inhalation NOAEL (PoD=2.68 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).
4-CPA Human Health Risk Assessment DP No. D419151

Page 16 of 32

10.0 Public Health and Pesticide Epidemiology Data

Adapted from: E. Evans and S. Recore, D421138, 06/26/2014

The OPP Incident Data System (IDS) and the Centers for Disease Control and 

Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event

Notification System for Occupational Risk-Pesticides (SENSOR) databases were consulted for 

pesticide incident data on the active ingredient 4-CPA, and salts (PC Code: 019401, 019402). 

The purpose of the database search is to identify potential patterns in the frequency and severity 

of the health effects attributed to 4-CPA, and salts exposure. 

Conclusions: There does not appear to be a concern at this time that would warrant further 

investigation, since there were no incidents involving 4-chlorophenoxyacetic acid (4-CPA), and 

salts reported to either IDS or SENSOR-Pesticides. The Agency will continue to monitor the 

incident information and if a concern is triggered, additional analysis will be performed.
4-CPA Human Health Risk Assessment DP No. D419151

Page 17 of 32

Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use of 4-CPA are in Table 1. Use of the new guideline numbers does 

not imply that the new (1998) guideline protocols were used.

Study

Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Acute Eye Irritation.......................................................

870.2500 Acute Dermal Irritation .................................................

870.2600 Skin Sensitization..........................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 90-Day Oral Toxicity in Rodents..................................

870.3150 90-Day Oral Toxicity in Nonrodents.............................

870.3200 21/28-Day Dermal Toxicity ..........................................

870.3250 90-Day Dermal Toxicity ...............................................

870.3465 90-Day Inhalation Toxicity ...........................................

yes

yes

yes

no

yes

yes

yes

yes a

---

yes a

870.3700a Prenatal Developmental Toxicity (rodent) ....................

870.3700b Prenatal Developmental Toxicity (nonrodent) ..............

870.3800 Reproduction and Fertility Effects ................................

yes

yes

yes

yes

yes a

yes a

870.4100a Chronic Toxicity (rodent)..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Carcinogenicity (rat)......................................................

870.4200b Carcinogenicity (mouse) ...............................................

870.4300 Combined Chronic Toxicity/Carcinogenicity ...............

yes

no

yes

yes

yes

yes a

---

yes a

yes a

yes a

870.5100 Mutagenicity—Bacterial Reverse Mutation Test..........

870.5300 Mutagenicity—Mammalian Cell Gene Mutation Test..

870.5375 Mutagenicity—In vitro mammalian cell assay..............

870.5385 Mutagenicity—In vivo cytogenetics..............................

870.5395 Mutagenicity—In vivo mouse micronucleus.................

yes

yes

yes

yes

yes

yes

yes

yes a

yes a

yes

870.6200a Acute Neurotoxicity Screening Battery (rat).................

870.6200b 90-Day Neurotoxicity Screening Battery (rat) ..............

870.6300 Developmental Neurotoxicity .......................................

yes

yes

yes

yes a

yes a

yes a

870.7485 Metabolism and Pharmacokinetics................................

870.7600 Dermal Penetration........................................................

870.7800 Immunotoxicity .............................................................

yes

yes

yes

yes a

yes a

yes a

a Although this study is normally required for a food-use chemical, HASPOC concluded the study can be waived

for 4-CPA (HASPOC memo finalized on 5/28/2014).
4-CPA Human Health Risk Assessment DP No. D419151

Page 18 of 32

A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Test Substance 

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [rat] 41837001 LD50 = 2703 

mg/kg

III

870.1200 Acute dermal [rabbit] 42522601 LD50 > 2000

mg/kg

III

870.1300 Acute inhalation [rat] 42968201 LC50 > 5.25 mg/L IV

870.2400 Acute eye irritation [rabbit] 42339101 Severe irritation I

870.2500 Acute dermal irritation [rabbit] 42306801 Non-irritating IV

870.2600 Skin sensitization [guinea pig] 42339102 Non-sensitizing NA

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile a

Guideline No./Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.3100a

90-Day oral toxicity 

rodents – rat

42902501 (1993)

Acceptable, guideline

0, 100, 2000, or 8000

ppm 

M: 0, 6.6, 132.4,

516.9 mg/kg/day

F: 0, 7.99, 153, 625.9

mg/kg/day

NOAEL = 132/153 mg/kg/day in males and females, 

respectively.

LOAEL = 517/626 mg/kg/day in males and females, 

respectively, based on decreased body weights in males and 

females and lymphohistiocytic infiltration and individual 

hepatocyte necrosis in males and increased urine volume in 

females.

870.3150b

90-Day oral (diet) 

toxicity 

non-rodents – dog

42968301 (1993)

Acceptable, guideline

0, 20, 100 or 500

ppm 

M; 0, 0.80, 3.3 and

18.6 mg/kg/day

F; 0, 0.78, 4.0 or

17.4 mg/kg/day

Average for males and

females; 0, 0.792, 3.67 

and 18.0 mg/kg/day.

NOAEL =18.6/17.4 mg/kg/day for males and females 

(HDT)

LOAEL = not observed

870.3200

28-Day dermal toxicity

– rat

- No study available or required a

870.3465

90-Day inhalation 

toxicity

- No study available or required a
4-CPA Human Health Risk Assessment DP No. D419151

Page 19 of 32

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile a

Guideline No./Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.3700a

Prenatal developmental

– rat

42322602 (1992)

Acceptable, guideline

F: 0, 150, 300, 600 or 

1000 mg/kg/day

Maternal NOAEL = 600 mg/kg/day

Maternal LOAEL = 1000 mg/kg/day based on mortality 

and clinical signs of neurotoxicity (tremors, uncoordinated 

movements, recumbent posture, languidness, and cold body, 

yellow staining of anogenital region)

Developmental NOAEL = 300 mg/kg/day 

Developmental LOAEL = 600 mg/kg/day based on 

unossified sternebrae and decreased fetal body weight

870.3700b

Prenatal developmental 

– rabbit

00144733 (1965)

Unacceptable, 

guideline

F: 0, 5, 10, 25 

mg/kg/day (rangefinding study, 5 

rabbits/group)

Maternal NOAEL = 25 mg/kg/day

Maternal LOAEL = not observed.

Developmental NOAEL = 25 mg/kg/day

Developmental LOAEL = not observed.

870.3800

Reproduction and 

fertility effects – rat

00083274 (1964)

Unacceptable, 

guideline

0, 25, 50, 250 ppm

0, 1.25, 2.5, 12.5 

mg/kg/day

Parental/Systemic NOAEL = 12.5 mg/kg/day 

Parental/Systemic LOAEL = not observed

Reproductive/Offspring NOAEL = 12.5 mg/kg/day 

Reproductive/Offspring LOAEL = not observed

870.4100a 

Chronic toxicity 

rodents

- No study available or required a

870.4200b

Carcinogenicity –

mouse

- No study available or required a

870.4300

Chronic toxicity/ 

Carcinogenicity – rat

- No study available or required a

870.5100

Bacterial reverse 

mutation test 

41837002 (1990)

Acceptable, guideline

0, 100-5000 μg/plate 

(+/-S9).

A dose range of 0-5000 μg/plate of 4CPA was used for 

strains TA98, TA100, TA 1535, TA 1537, and TA 1538 of 

S. typhimurium. The test was negative up to cytotoxic doses 

of 5000 μg/plate with no activation (-S9), and up to doses of 

5000 μg/plate with activation (+S9) where no cytotoxicity 

was seen.
4-CPA Human Health Risk Assessment DP No. D419151

Page 20 of 32

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile a

Guideline No./Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.5300

Mouse lymphoma 

cell/mammalian 

activation gene forward 

mutation assay 

(L5178Y HGPRT) 

41837004 (1991)

Acceptable, guideline

100, 500, 1000, 1600, 

2000, 2500, 3000, 

3500, or 4000 μg/mL 

(-S9)

10, 50, 100, 250, 300, 

750, 1000, 1300, 1600, 

or 2000 μg/mL (+S9)

4-CPA (99%) was evaluated for potential to induced

forward mutations at the TK+/- locus in L5178Y TK+/-

cells in two independently performed trials. Without S9

activation, 4-CPA was not mutagenic at doses up to 4000

μg/mL: higher levels (5000 μg/mL) were severely

cytotoxic. In the presence of S9 activation at 10, 50, 100,

250, 300, 750, 1000, 1300, 1600, or 2000 μg/mL

(cytotoxic at doses 1300 μg/mL), non-dose related

increases in mutation frequency (MF) were obtained in

both trials. Although there was a tendency for elevated

MFs at doses ranging from 300 to 1600 μg/mL +S9,

doubling of the MF over concurrent controls was only

seen at 600 μg/mL (Trial 1) and 1000 μg/mL (Trial 2). 

The evidence suggesting a mutagenic response, was 

however, insufficient to conclude the 4-CPA was positive. 

The test material was not mutagenic in this in vitro

mammalian cell assay.

870.5375

In vitro mammalian 

cell assay

- No study available or required a

870.5385

In vivo cytogenetics - No study available or required a

870.5395

In vivo mouse 

micronucleus

41837003 (1991)

Acceptable, guideline

M & F: 0, 0, 450, 900 

or 1800 mg/kg

In an ICR mouse bone marrow micronucleus assay,

5/sex/group were treated gavage with 4-CPA (99%) at

doses of 0, 450, 900 or 1800 mg/kg-bw. Bone marrow

cells were harvested at 24, 48, and 72 hours posttreatment.

There were signs of toxicity, languidness and prostration,

and most animals died within 24 hours at 1800 mg/kg

during the study. Hematopoiesis was adversely affected at

1800 mg/kg. There were 5000 polychromatic erythrocytes

and < 5 micronucleated polychromatic erythrocytes (MPE) 

per group with no dose response. 4-CPA was tested at an

adequate dose based on mortality. The positive control

induced the appropriate response. There was no

significant increase in the frequency of micronucleated 

polychromatic erythrocytes in bone marrow after any

treatment time.

870.6200a

Acute Neurotoxicity 

with parent – rat

- No study available or required a

870.6200b

Subchronic 

neurotoxicity screening 

battery – rat

- No study available or required a

870.6300

Developmental 

neurotoxicity study –

rat

- No study available or required a
4-CPA Human Health Risk Assessment DP No. D419151

Page 21 of 32

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile a

Guideline No./Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.7485

Metabolism and 

pharmacokinetics – rat

- No study available or required a

870.7600

Dermal penetration -

rat

- No study available or required a

870.7800 

Immunotoxicity – rat - No study available or required a

a No other toxicity studies (including conditionally required studies) are available. HASPOC has determined that the studies 

which are typically required for a food-use pesticide are not required for 4-CPA (HASPOC memo finalized on 5/28/2014).
4-CPA Human Health Risk Assessment DP No. D419151

Page 22 of 32

Appendix B: Toxicity Studies with 4-chlorophenoxyacetic acid (4-CPA) and Structures

Related to 4-CPA.

The following are brief summaries of the cancer findings for each of the structural 

analogs for which there are studies. In some cases the Cancer Assessment Review Committee 

(CARC) has not evaluated the pesticide. Comparison of the results from toxicity studies are 

made for 4-CPA and the four analogs, 2,4-dichlorophenoxyacetic acid, 2-methyl-4-

chlorophenoxyacetic acid, 3-chlorophenoxy-2-propionic acid, and 2-methyl-4-

chlorophenoxybutyric acid ( Table 1). More structurally remote chlorophenoxy acid pesticides 

are: (1) 2,4-dichlorophenoxybutyric (not carcinogenic in rats or mice), (2) 2,4-dichlorophenoxy2-propionic acid (not carcinogenic in rats or mice), (3) 2,4,5-trichlorophenoxyacetic acid 

(evidence of carcinogenicity in total tumors in female mice, but not rats), and (4) 2,4,5-

trichlorophenoxy-2-propionic acid (no studies available). These latter pesticides are not shown 

and not summarized further. [Information from Carcinogenicity Peer Review (4th) of 2,4-D, 

1/29/97.]

Structure of 4-chlorophenoxyacetic acid (4-CPA) (PC 019401)

Although there are no carcinogenicity studies on 4-CPA, the weight of the 

evidence does not suggest that 4-CPA would be carcinogenic in life-time 

studies at reasonable doses not causing excessive toxicity.

Structure of 2,4-dichlorophenoxyacetic acid (2,4-D)(PC 030001)

The following is a summary of the findings from the fourth and 

last cancer assessment of 2,4-D. This pesticide has the largest toxicity data 

base of all the analogs. The Cancer Peer Review Committee (CPRC) 

concluded that 2,4-D should remain classified as a “Group D” — Not 

classifiable as to a human carcinogenicity. That is, the evidence is 

inadequate and cannot be interpreted as showing either the presence or the absence of a 

carcinogenic effect.

2,4-D was initially classified as a possible human carcinogen, based on a significant 

increased trend for brain astrocytomas in male Fisher 344 rats and suggestive to weak and 

conflicting evidence of non-Hodgkin’s lymphoma from several epidemiological studies. There 

was no evidence of tumor induction in female rats or male or female B6C3F1 mice, however, the 

CPRC concluded that the highest dose tested in both studies was sufficiently toxic to adequately 

test for carcinogenicity. Repeat studies were conducted in rats and mice at adequate doses, but 

neither study showed statistically significantly increased tumor incidence in either species or sex.

Mutagenicity studies showed consistently negative results without activation and positive 

and negative result with activation. The CPRC concluded that although cytogenic activity was 

seen, there was no concern for mutagenicity.

Metabolism studies in the rat indicated that 85 to 94% of the parent was excreted 

unchanged in the urine with 0% -1.3% of 2 uncharacterized compounds and 4 to 10% was 

excreted as the parent in feces. Total excretion (98 to 99.5%) occurred within 48 hours.

The CPRC and SAP agreed on a “Group D” classification.

[Information from Carcinogenicity Peer Review (4th) of 2,4-D, 1/29/97.]
4-CPA Human Health Risk Assessment DP No. D419151

Page 23 of 32

Structure and results on 2-methyl-4-chlorophenoxyacetic acid (MCPA)

(PC 030501)

MCPA has not been reviewed by the CARC, but a toxicology 

reviewer indicated that no dose related tumors were seen in rats or mice at 

adequate doses to test for carcinogenicity.

A battery of mutagenicity studies shows a positive study for chromosomal aberrations in 

human lymphocyte cells and weakly mutagenic response in an in vivo sister chromatid exchange 

study. The remaining 6 in vivo and in vitro mutagenicity studies conducted were negative.

The metabolism studies in the rat shows that MCPA is excreted in the urine (74-86%; 

53%-69% as the parent and 7-13% as the hydroxymethyl metabolite and 2-5% in the feces). 

Total excretion occurred within 192 hours (98%).

[Information from the 1-liners and Paul Chin reviewer].

Structure and results on sodium 3-chlorophenoxy-2-propionate (cloprop, sodium salt)

(PC 021201)

Life-time carcinogenicity studies have been conducted with cloprop, 

but there are no definitive conclusions. There was a statistically 

significantly increasing trend and pair-wise comparison with control for 

mortality in male and female rats at the top dose. The registrant refused to 

submit historical control data on morality among the rats used in the 

carcinogenicity study. Consequently the Peer Review of cloprop was canceled and the pesticide 

withdrawn.

In the mouse study, there was statistically significantly pair-wise comparison of male 

liver adenomas/carcinomas and male liver carcinomas at the highest dose tested and in females 

for liver adenomas and carcinomas at the two lowest doses tested, but not at the highest dose 

tested. One reviewer believed that there was no evidence for carcinogenicity in mice, however 

another reviewer believed there was evidence of liver cancer in mice. The issue has never been 

resolved because the pesticide was withdrawn.

Cloprop is negative in a battery of mutagenicity studies.

There are no metabolism studies in rats, but in goats, cloprop is excreted as the parent.

[Information from 1-liners and a memorandum from John Redden.]

Structure and results on 2-methyl-4-chlorophenoxybutyric acid (MCPB) (PC 019201)

No life-time carcinogenicity studies have been conducted with MCPB.

A battery of mutagenicity studies are negative. One study for 

chromosomal abnormalities with S9 produced chromosomal abnormalities at 

high doses.

There are no adequate metabolism studies, but a reference from the 

literature suggest that bacteria split off acetic acid from the butyric acid residue in plants and 

cows.

[Information from 1-liners and DERs.]

Structure and results on 2(4-chlorophenoxy)-2-methylpropanoic acid ethyl ester;

the Drug Clofibrate (lowers plasma triglycerides and cholesterol)
4-CPA Human Health Risk Assessment DP No. D419151

Page 24 of 32

An International Agency for Research on Cancer (IARC) Monograph on clofibrate states 

that there is inadequate evidence in humans for carcinogenicity and limited evidence in animals 

for carcinogenicity.

Clofibrate is peroxisome proliferator and is excreted rapidly in human urine as the parent. 

(http://193.51.164.11/htdocs/monographs/vol66/clofibrate.html).

Structure and results on mecoprop [2-(2-methyl-4-chlorophenoxy)propionic acid]

(PC 031501)

The acute toxicity of mecoprop is similar to that of 4-CPA. The

NOAEL/LOAEL in the rat 90-day feeding study was lower than the 

NOAEL/LOAEL in rat 90-day neurotoxicity study, which showed no 

neurotoxic effects, in addition to being lower than 4-CPA in a rat 90-day 

feeding study. A rabbit developmental toxicity study showed a maternal 

NOAEL/LOAEL of 30/75 mg/kg/day, but no developmental toxicity at the highest dose tested. 

The rat developmental toxicity study showed developmental toxicity in the form of decreased 

crownrump lengths, decreased ossification of sternebrae and increased intrauterine death at the 

highest dose tested, which was a maternally toxic dose. The rat developmental effects occurred at 

a lower dose than the effects from 4-CPA in a rat developmental toxicity study. No 90-day 

feeding study in dogs is available.

Potential carcinogenic effects have not been fully evaluated as yet, but there is suggestive 

evidence for increased liver tumors in mice. The rat carcinogenicity study was negative.

A reverse gene mutation study was acceptable and negative and chromosomal aberrations 

study was acceptable and negative for clastogenicity (MRID# 41013909, TXR# 009589). The 

remaining mutagenicity studies were unacceptable.
4-CPA Human Health Risk Assessment DP No. D419151 

Page 25 of 32 

Table I: Comparison of toxicity studies/results for 4-chlorophenoxyaoetic acid ( 4-CPA) and four analogs of 4-CPA 

ru t 4-c -ph~n xy c~ric -dicblor ph~n 2- 2-~ y1-4- hl ro- sodium (3- thyl

acid (4-CPA) ac~ric acid (2,4-D) ph~n 2-ac~ric add rop ~n y) -2- ch roph y)

019401 030001 (i\ICPA) pion ~ butyric acid (l\ICPB) Data fromDERs & ~•· Data from 1-Lin~r & ~r 030501 (d oprop, sodium salt) 019201 R~,. Y Data from Lin~r & 021201 Da ta from -Lin~r Paul Chin Data fr om Lin~r 

No info in Archiws 

CI'Q CI'C( Clv 

I : o"l(o" ~ 

co 

CH ~c~ 

~ 

o & "l(OH & if'YOH oA.YOH• 0 0 CH, 0 0 0 

Results on (a.i.) Results on (a.i.) Results on (a.i.) Results on (a.i.) Results on (a.i.) 

870.1100 Acute Oral ToxicitylD50 2703 mg/kg 3 73 Omg/kg 3500 mg/kg 1567 mg/kg 1570 mg/kg 

870.1200 Acute Dermal 

Toxicity/ID50 >2000 mg/kg >2000 mg/kg >2000mg/kg - I 000 mg/kg 

870.1300 Acute Inhalation 

Toxicity/LC50 >5 .25 mg/L > 1.8 mg/L 4hr > 6.3 mg/L - 1.1 mg/L (acetone 

870.2400 Primary Eye Irritation . Severe Mod/Severe Mod/Severe - vehicle) 

870.2500 Primary Dermal Irritation Not irritating None Irritating Slight - Mod/Severe 

870.2600 Dermal Sensitization Not sensitizing Not sensitizing Not sensitizing - -

-

870.3100 Oral Subchrooic (rat) . NIL=i52/517mkd, Bwt NIL=i 5/100mkd testes, NIL=501150ppm - NIL=158/-mlk/d HDT 

dec & urine volume liver, thyroid weight inc & NIL=2.5n .5 mkd inc palatability noted; 

inc, liver individual spleen histop kidney weight with incr kidney weight incr, 

cell necrosis creatinine HDT, no ltistop neg 

ltistop 

870.3150 Oral S ub chronic (dog) . NIL=18.6/-mkd HOT N/L=i.0/3.0 mkd, liver, N IL=O. 6/2 .4 mkd liver NIL=l2.5/50 mkd, NIL= 12/40mkd Inc BS P 

(Peer Rev); kidney & testes ltisto intlanuuation & clinical bwt deer, liver, retention, dec 

NIL=3.3/ 19mkd bwt & chemistry (MCPA- kidney & spleen spemtatogeoic activity, 

food deer; no histop Dinteth ylainine) weightincr prostate & testes rubular changes seen (DER) atrophy 

870.3200 21-Da.y Dermal (rabbit) . - NIL= 1000/-mkd SystNIL=IOO/IOOOmkd 

Mineralization kidney 

- -

tubules 

IrritatiouNIL= 

870.3250 90-Da.y Dermal . . . . · · · · - - - 10/iOOmkd - - 870.3465 90-Da.y Inhalation . . · · · · - - - - -
4-CPA Human Health Risk Assessment DP No. D419151

Page 26 of 32
4-CPA Human Health Risk Assessment DP No. D419151

Page 27 of 32
4-CPA Human Health Risk Assessment DP No. D419151

Page 28 of 32
4-CPA Human Health Risk Assessment DP No. D419151 

Page 29 of 32 

Study!T~st 4-<h oro-ph~noxy ~ric 2,4-dichloroph~no~")-2- (2 -~ hyl-4 chloro- sodium (3- (2- ~thylacid (4-CPA) ac~ric acid (2,4-D) ph~no~}2-ac~ric acid ch oroph~noxy) -2- oph~noxy

019401 030001 (i\ICPA) prop onat~ butyric acid (l\ICPB) Data from DI Rs & ~r Data from Lin~r & ~r 030501 (doprop, sodium salt) 019201 ~,- R~Y Data from Lin~r & 021201 Data from -Li ~r Paul Chin Data from Li ~r 

No info in Archiws 

~ CI'C( CI'Gl co <>< 

I : 0-"J(oH I : ifj(CH ~ CH 0 ~c~ o & -"J(CH oAYOH' 0 0 CH, 0 0 0 

870.7485 General Metabolism (L~b# - Excreted as parent in urine Mostly excreted as Excreted as parent, Lit.; Bact-Splits off 

1521517) (86-94%), 4-11% in the MCPA, 7-13% mostly acetic acid from the 

feces hydroxylated me.thyl wunetabolized in the butyric acid residue in Small amooots of MCPA. 98%excreted goat plants and cows metabolites (0.6%-1.3%). within 192 hr. uc UA 

98-99.5% recovered Excreted mostly llllwithin 48 hr. metabolized 

Excreted mostly tmmetabolized 

870.7600 Dermal Penetration - - - - -

Carcogenicity No studies "D" not classifiable as a Classification ... human carcinogen Not likely to be a hlllll3U 

carcinogen, but no HIARC: 

Rats (historical control 

required) Chem 

No carcinogenicity studies 

or CARC review yet withdrawn 

Mice increased pair- wise hepatocellular carcinomas at HDT 

Unclassified by C;\RC 

1 This 3-geueratiou reproduction study with 4-CP A is reasonably well conducted but the. doses were too low (the highest dose tested was 12.5% of the NO;\EL fron1 the 90-day subchronic study in 

rats.). The. highest dose tested was 250 ppm and the. NOAEL in a 90-<lay rat smdy was 2000 ppm. In addition, the. colony showed respiratory problems with weight loss with recovery and related 

marked cannibalism, and pup death due to maternal death. The material tested appeared to be reasonably pure from acid equivalent measuren1euts, but since no units were. reported, this c3llllot be 

verified. The study was conducted prior to GLPs and the test material in the diet was not measured. Therefore the study is tmacceptable/not upgradable. 

NIL = NOAELILOAEL followed by effects at LOAEL unless otherwise specified; mkd = mglkg/day. -=No smdy conducted or available; UA = Unacceptable smdy; UC = Unclassified smdy; 

a.i. = active ingredient. inc=increase; dec=decrease; histop=histopathology; DER= data evaluation record; neg=ne.gative; pos=positive; Syst=systemic; HDT=highest dose tested; mod=moderate; 

Bwt=body weight; unoss=tmossified; oss=ossification; M=materual; D=developmental; UA=unacceptable; P=parental; O:ff=offspring; FOB=FunctiOflal Observation Battery; CARC=Cancer 

Assessment Review Committee. 
4-CPA Human Health Risk Assessment DP No. D419151

Page 30 of 32

Appendix C. Physical/Chemical Properties

Table C1. Physico-Chemical Properties1

Parameter Value Reference

Molecular Weight 186.59

Lide, D.R., G.W.A. Milne (eds.). Handbook 

of Data on Organic Compounds. Volume I. 

3rd ed. CRC Press, Inc. Boca Raton ,FL. 

1994., p. V1: 115

Water solubility (25°C) 957 mg/L 

Yalkowsky, S.H., He, Yan., Handbook of 

Aqueous Solubility Data: An Extensive 

Compilation of Aqueous Solubility Data for 

Organic Compounds Extracted from the 

AQUASOL dATAbASE. CRC Press LLC, 

Boca Raton, FL. 2003., p. 461

Vapor pressure (25°C) 3.2x10-4 mm Hg EPA; Estimation Program Interface (EPI) 

Suite. Ver.3.12. Nov 30, 2004

Dissociation constant, pKa 3.56 Bailey GW, White JL; Res Rev 10: 97-123 

(1965)

Octanol/water partition coefficient, log KOW

(25°C) 2.25

Hansch, C., Leo, A., D. Hoekman. Exploring 

QSAR - Hydrophobic, Electronic, and Steric 

Constants. Washington, DC: American 

Chemical Society., 1995., p. 38

1

Information obtained from ToxNet on 2/25/2014 (http://toxnet.nlm.nih.gov/cgibin/sis/search/a?dbs+hsdb:@term+@DOCNO+3944). Original references specified in the website were included.
4-CPA Human Health Risk Assessment DP No. D419151

Page 31 of 32

Appendix D. Chronic Dietary Assessment for 4-Chlorophenoxyacetic Acid

Input File

US EPA Ver. 3.16, 03-08-d

DEEM-FCID Chronic analysis for 4-CHLOROPHENOXYACETIC ACID

Residue file: F:\Dietary Assessments\4-CPA\4CPA_Dietary_chronic.r08

 Adjust. #2 NOT used

Analysis Date 05-21-2014 Residue file dated: 05-21-2014/11:36:45

Reference dose (RfD) = 1.32 mg/kg bw/day

Comment:Mung Beans only; no EDWCs due to limited use

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

Food Crop Residue Adj.Factors

EPA Code Grp Food Name (ppm) #1 #2 

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

0603039000 6C Bean, mung, seed 0.200000 1.000 1.000 

Results File

US EPA Ver. 3.16, 03-08-d

DEEM-FCID Chronic analysis for 4-CHLOROPHENOXYACETIC ACID NHANES 2003-2008 2-day

Residue file name: F:\Dietary Assessments\4-CPA\4CPA_Dietary_chronic.r08

 Adjustment factor #2 NOT used.

Analysis Date 05-21-2014/11:37:12 Residue file dated: 05-21-2014/11:36:45

Reference dose (RfD, Chronic) = 1.32 mg/kg bw/day

COMMENT 1: Mung Beans only; no EDWCs due to limited use

===============================================================================

 Total exposure by population subgroup

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

 Total Exposure

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

 Population mg/kg Percent of 

 Subgroup body wt/day Rfd 

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

Total US Population 0.000000 0.0%

Hispanic 0.000000 0.0%

Non-Hisp-White 0.000000 0.0%

Non-Hisp-Black 0.000000 0.0%

Non-Hisp-Other 0.000003 0.0%

Nursing Infants 0.000000 0.0%

Non-Nursing Infants 0.000000 0.0%

Female 13+ PREG 0.000000 0.0%

Children 1-6 0.000000 0.0%

Children 7-12 0.000000 0.0%

Male 13-19 0.000001 0.0%

Female 13-19/NP 0.000000 0.0%

Male 20+ 0.000001 0.0%

Female 20+/NP 0.000000 0.0%

Seniors 55+ 0.000000 0.0%

All Infants 0.000000 0.0%

Female 13-50 0.000000 0.0%

Children 1-2 0.000000 0.0%

Children 3-5 0.000000 0.0%

Children 6-12 0.000000 0.0%

Youth 13-19 0.000001 0.0%

Adults 20-49 0.000001 0.0%

Adults 50-99 0.000000 0.0%

Female 13-49 0.000000 0.0%

-------------------------------------------------------------------------------
4-CPA Human Health Risk Assessment DP No. D419151

Page 32 of 32

Appendix E. International Residue Limits 

4-Chlorophenoxyacetic acid (PC Code 019401)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex

40 CFR 180.202:

(a) General. A tolerance is established for the 

combined residues of the plant regulator pchlorophenoxyacetic acid and its metabolite pchlorophenol to inhibit embryonic root 

development.

(4-chlorophenoxy) 

acetic acid

None

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex

Bean, mung, sprouts 0.2 2

Completed: M. Negussie; 02/06/2014

1

Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and 

not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.