Docket Number EPA-HQ-OPP-2010-0673 

www.regulations.gov 

d-Limonene 

Proposed Interim Registration Review Decision 

Case Number 3083 

September 2015 

Approved by: 8=::!1~ ~ ,<:(h 

Richard P. Keigwin, Jr. 

Director 

Pesticide Re-evaluation Division 
Table of Contents 

Contents 

I. Introduction ............................................................................................................................. 3 

II. Scientific Assessments ............................................................................................................ 6 

A. Human Health Assessment .................................................................................................... 6 

Hazard and Dietary Risk Analysis .......................................................................................... 6 

Aggregate (Dietary+ Non-occupational) Exposure and Risks ............................................... 7 

Human Incidents ..................................................................................................................... 7 

B. Environmental Assessment ................................................................................................... 7 

Environmental Fate and Exposure .......................................................................................... 7 

Ecological Risk Characterization ............................................................................................ 7 

Endangered Species Assessment ............................................................................................ 8 

Ecological Incidents ................................................................................................................ 9 

C. Endocrine Disruptor Screening Program ......................................................................... 10 

III. Risk Characterization and Proposed Interim Registration Review Decision .................... 11 

IV. Next Steps and Timeline .................................................................................................... 14 

Appendix A: Summary of Actions Taken for d-Limonene ......................................................... 15 

Appendix B: d-Limonene Label Table ........................................................................................ 16 

References ..................................................................................................... 1 7 

2 
I. Introduction 

This document is the Environmental Protection Agency's (EPA or the Agency) Proposed 

Interim Registration Review Decision for d-limonene and is being issued pursuant to 40 CFR 

sections 155.56 and 155.58 (Registration Review Case Number 3083, PC Codes 079701 and 

179701). A registration review decision is the Agency's determination whether a pesticide meets, 

or does not meet, the standard for registration in the Federal Insecticide, Fungicide, and 

Rodenticide Act (FIFRA). The Agency may issue, when it determines it to be appropriate, a 

proposed interim registration review decision before completing a registration review. Among 

other things, the proposed interim registration review decision may require new risk mitigation 

measures, impose interim risk mitigation measures, identify data or information required to 

complete the review, and include schedules for submitting the required data, conducting the new 

risk assessment and completing the registration review. For further information on d-limonene, 

additional documents can be found in EPA's public docket (EPA-HQ-OPP-2010-0673) at 

www.regulations.gov. 

FIFRA, as amended by the Food Quality Protection Act (FQPA) of 1996, mandated the 

continuous review of existing pesticides. All pesticides distributed or sold in the United States 

generally must be registered by the EPA based on scientific data showing that they will not cause 

unreasonable risks to human health or to the environment when used as directed on product 

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

and reduce risk evolves and as policies and practices change, all registered pesticides continue to 

meet the statutory standard of no unreasonable adverse effects. Changes in science, public 

policy, and pesticide use practices will occur over time. Through the registration review 

program, the Agency periodically re-evaluates pesticides to make sure that as these changes 

occur, products in the marketplace can continue to be used safely. In 2006, the Agency 

implemented the registration review program pursuant to FIFRA section 3(g) and will review 

each registered pesticide every 15 years to determine whether it continues to meet the FIFRA 

standard for registration. Information on this program is provided as 

www.epa.gov/oppsrrdl/registration review/. 

d-limonene was first registered as an insecticide in 1958 and as an antimicrobial product 

in 1971. The reregistration eligibility decision (RED) for d-limonene was issued in 1994 and the 

tolerance reassessment eligibility decision (TRED) was issued in 2005 . In September 2010, the 

Agency initiated the registration review for d-limonene (case 3083) with the opening of the dlimonene registration review public docket (docket no. EPA-HQ-OPP-2010-0673 , accessible at 

www.regulations.gov). 

d-limonene occurs naturally in citrus and certain fruits, vegetables, meats, and spices. It is 

used as both an active and inert ingredient in pesticide products, and as an ingredient in food 

products, cleaning products, soaps, and perfumes. d-Limonene is registered for use in/on 

terrestrial food, feed crops, non-food crops, and for residential uses. Pesticide products 

containing d-limonene as an active ingredient are registered for use as insecticides, herbicides, 

and insect repellents. As a pesticide inert ingredient, it is used as a solvent or fragrance. Nonpesticidal uses of d-limonene include use in solvents (such as a substitute for chlorinated 

hydrocarbons, chlorofluorocarbons); use as a degreaser; or as a cleaning agent such as for 

3 
industrial and household uses. Currently, the only antimicrobial uses of d-limonene are as an 

inert ingredient and are not subject to registration review. 

The following list highlights significant events of the registration review of d-limonene. 

These documents and additional information on d-limonene can be found in EPA's public 

docket, EPA-HQ-OPP-2010-0673 , accessed at www.regulations.gov. 

• 09/17110 - Publication of d-limonene Summary Document for a 60-day public comment 

period. The Summary Document included the Preliminary Work Plan (PWP) and was 

accompanied by the Scoping Document and Problem Formulation. 

• 01 /24/11 - Publication of the Final Work Plan (FWP) for d-limonene was issued -- no 

public comments were received during the 60-day comment period for the d-limonene 

PWP; thus, the FWP did not modify the PWP. 

• 01/12/2011 - Generic Data Call-In (GDCI) for d-limonene issued. Data required through 

the d-limonene registration review GDCI include. 

o GLN 850.4100: terrestrial plant toxicity (seedling emergence) 

o GLN 850.4150: terrestrial plant toxicity (vegetative vigor) 

o GLN 850.4400: aquatic plant toxicity 

o GLN 850.5400: algal toxicity 

• 12/24/2014 - The Agency published the Preliminary Ecological Risk Assessment for the 

Registration Review of d-limonene and the Registration Review Preliminary Human 

Health Risk Assessment for d-limonene for a 60-day public comment period. Five 

comments were received during the comment period. 

Comments were submitted by the Center for Biodiversity (CBD) and from the general public. 

Of the comments submitted by the general public, three were anonymous, one did not reference 

d-limonene, one was with regard to pet products that contain d-limonene, and one was a link to 

an expired petition. 

Comment: The Center for Biological Diversity (CBD) comment focuses on EPA's 

independent duty under the Endangered Species Act (ESA) to consult with the U.S. Fish 

and Wildlife Service and the National Marine and Fisheries Service (collectively, the 

Services) on the registration review of d-limonene. Specifically, CBD opposes the 

proposed decision for d-limonene prior to completion of consultation with the Services. 

EPA Response: EPA has reviewed the comments from CBD on the registration review 

docket opening for d-limonene and plans to address many of the concerns raised by CBD 

as part of the implementation plan for assessing the risks of pesticides to listed species 

based on the recommendations of the April 2013 National Academy of Sciences (NAS) 

report. EPA will address concerns specific to d-limonene in connection with the 

development of its final registration review decision for d-limonene, see Appendix B for 

additional information. 

4 
Comment: One submission (EPA-HQ-OPP-2010-0673-0022) commented against the 

continued registration of pet products that contain d-limonene. That submission included 

aggregate incident information on d-limonene. 

EPA Response: In response to the comment and information provided under this 

submission, the Agency conducted a review of the Incident Database System (IDS) for 

adverse events associated with domestic animals and pesticide products that contain dlimonene. The Agency also obtained additional information from the technical registrant. 

Based upon its incident review, and information provided by the registrant, the Agency 

does not believe pet products that contain d-limonene pose an unreasonable risk, but that 

potential risk to domestic animals could be reduced through changes to product labeling. 

Therefore, the Agency discussed label changes with the registrant, and is including them 

in this Proposed Interim Decision, see section III, Proposed Interim Registration Review 

Decision. The Agency's incident summary document, Limonene and d-Limonene : 

Review of Domestic Animal Incidents, dated August 25, 2015 and the Agency's full 

response to this comment, d-Limonene: PRD Response to Comments on Registration 

Review Preliminary Risk Assessment, dated September 15, 2015 can be found in the 

public docket, EPA-HQ-OPP-2010-0673 , accessed at http://www.regulations.gov/. 

Comment: One anonymous submission (EPA-HQ-OPP-2010-0117-0019) commented on 

the serious health risks (respiratory) from d-limonene with references to several studies 

and a novel. 

EPA Response: The Agency utilizes its Incident Data System (IDS) as well as several 

other databases to monitor adverse health outcomes due to pesticide exposure. With 

regard to pesticide products that contain d-limonene, the Agency completed an informal 

review of incidents since 2010 (M. Perron; Aug 2015). The Agency's report dated 

August 24, 2015 indicated 19 reported incidents of minor severity, 3 of which were 

associated with respiratory symptoms. The Agency also conducted an updated review of 

the SENSOR database (i.e. the Sentinal Event Notification System for Occupation Risk 

Pesticides) which is an incident database that draws from different sources (Poison 

Control Centers, the State Department of Labor, State Departments of Agriculture and 

State Departments of Health) and is maintained by the Centers for Disease 

Control/National Institute for Occupational Safety and Health. Within SENSOR, 17 

incidents were reported, 3 of which were associated with respiratory effects. Therefore, 

based on its review of current data bases, the Agency believes that the low frequency and 

low severity of human health incidents does not warrant concern at this time. The Agency 

will continue to monitor incident information in the future. The referenced incident 

reports can be found in the public docket EPA-HQ-OPP-2010-0673 at 

www.regulations.gov. 

• 6/24115 - The Agency is now publishing the d-Limonene Proposed Interim Registration 

Review Decision, dated September 2015 for a 60-day public comment period. 

5 
Use and Usage 

As an herbicide, d-limonene is a non-systemic, contact herbicide that strips the waxy rind or 

cuticle from plants causing death of the plant by desiccation 1

• As an insecticide, d-limonene 

affects the sensory nerves and it is used for flea and tick control in pet products, as an insecticide 

spray, and other insect-repellant products. Formulations include ready-to-use solutions, 

emulsifiable concentrates, granulars and impregnated material. National level usage data on dlimonene is unavailable. The only usage data on d-limonene is reported by California DPR 

which showed an average of 50,000 lbs./yr on agricultural crops. 

II. Scientific Assessments 

A. Human Health Assessment 

A summary of the Agency's human health risk assessment is presented below. The 

Agency considered the most updated science policies and risk assessment methodologies when 

considering the human health analysis of d-limonene for registration review. For a detailed 

discussion, see the d-Limonene Human Health Risk Assessment in Support of Registration 

Review, published on December 24, 2014 in the public docket EPA-HQ-2010-0673 which can be 

accessed on http://www.regulations.gov/. 

Hazard and Dietary Risk Analysis 

d-Limonene has been evaluated in numerous assays since the 1950s, and found to be of 

low hazard. The U.S. Food and Drug Administration (FDA) has identified d-limonene to be 

Generally Recognized as Safe (GRAS) as a food additive when used as a synthetic flavoring 

substance and adjuvant (21 CFR § 182.60). Because of its low toxicity, the Agency determined 

that additional human health toxicity data (including neurotoxicity data and immunotoxicity 

data), were not needed to support the registration review of d-limonene. Human health toxicity 

points of departure have not been selected for any population subgroup, or for any route or 

duration of potential exposure for d-limonene. Therefore, based upon the low toxicity of dlimonene, absence of toxicity endpoints, and the classification of d-limonene as GRAS by FDA, 

the Agency determined that a quantitative human health analysis was not warranted. 

Consequently, a dietary (food and drinking water) assessment was not conducted 

Occupational and Residential Risk 

Based upon the low toxicity of d-limonene and absence of toxicity endpoints, the Agency 

determined that neither an occupational (handler or worker) nor a residential (handler or post 

application) assessment was warranted. 

1 Stephen 0. Duke, Joanne G. Romagni, Franck E. Dayan 2000. Natural products as sources for new mechanisms of herbicidal action. Crop 

Protection 19 (2000) 583 -589. 

6 
Aggregate Exposure and Risks 

Due to the Agency's decision not to conduct either a dietary or a residential risk 

assessment for d-limonene, an aggregate risk assessment was not needed. 

Food Tolerances 

Because no points of departure have been identified for d-limonene, the Agency has not 

established any food tolerances for d-limonene. Under 40 CFR 180.539, a general exemption for 

d-limonene has been granted noting that the insecticide d-limonene may be used safely in insectrepellent tablecloths and in insect-repellent strips in food or feed handling establishments. In 

addition, there are no established Codex or Mexican Maximum Residue Limits (MRLs) for dlimonene. 

Human Incidents 

A summary report listing adverse human health incidents identified in the Office of 

Pesticide Program Incident Data System (IDS) for d-limonene was completed in 2010 

representing incident data between 2002 to 2009. The Agency identified 44 incidents that 

involved d-limonene, but d-limonene was only identified as the sole active ingredient in 6 

incidents. In response to public comments received on the Preliminary Risk Assessment, the 

Agency conducted an updated incident review, dated August 24, 2015. In both reviews, the 

Agency found that cases involving d-limonene to be of low frequency, of low severity, and do 

not indicate a trend or pattern. 

B. Environmental Assessment 

There are approximately 23 pesticide products that contain d-limonene as the active 

ingredient. However, when assessing potential ecological risk from this compound, the Agency 

focused on the products with the highest application rates and application frequencies which 

would lead to the highest environmental exposure and risk. A summary of the Agency's 

environmental risk assessment for d-limonene is presented below. For detailed discussions of all 

aspects of the environmental risk assessment, see the d-Limonene: Ecological Risk Assessment 

for Registration Review, in docket EPA-HQ-OPP-2010-0673 , which can be accessed at 

http://www.regulations.gov/. 

Environmental Fate and Exposure 

d-limonene is volatile and has a low solubility and low mobility in soil. It is 

photodegradable in air, biodegradable under aerobic conditions, and stable to hydrolysis. The 

major route of dissipation for d-limonene is volatilization. Other dissipation processes include 

photodegradation in air, microbial-mediated aerobic soil metabolism, sorption to soil, and 

transport in runoff water. 

Ecological Risk Characterization 

7 
Terrestrial Species 

Although d-limonene is practically non-toxic to mammals, high application rates resulted 

in acute and chronic risk quotients (RQ) above the level of concern (LOC), where acute RQs 

ranged from <LOC - 7.98 (where the LOC is 0.5). Chronic RQs ranged from <LOC - 140.37, 

(where chronic LOC is 1). 

Effects were not identified in the acute toxicity studies with birds and consequently acute 

risk quotients (RQ) were not estimated. Chronic RQs were also not calculated due to a lack of 

data. 

Risks to terrestrial invertebrates, for which the honey bee is the surrogate, were also not 

estimated due to the lack of data. However, in June 2014, the Agency issued its Guidance for 

Assessing Pesticide Risks to Bees2, and the Agency has begun to require these data where 

applicable. In order to understand the potential risk of d-limonene to terrestrial invertebrates, the 

Agency intends to require pollinator data with d-limonene in the future. 

With respect to non-target terrestrial plants, estimated RQs for plants at the edge-of-thefield (i.e., exposed to runoff) range from< LOC - 2.91 (where plant LOC is~ 1). Based upon 

drift analysis, the distance from the edge-of-field to the point at which no effects to non-target 

terrestrial plants is expected, ranged from 0 - 19 feet for non-listed species and up to 305 feet for 

listed species. 

Aquatic Species 

The Agency estimated acute RQs for freshwater fish and freshwater invertebrates which 

were all well below the LOC (LOC :S 0.5). The Agency did not estimate acute RQs to estuarine 

species due to a lack of data, but based upon a conservative analysis, expects that acute risk to 

these species would also be low. In its conservative analysis, the Agency compared the highest 

estimated environmental concentration to the lowest toxicity value, and found that fish would 

need to be 379 times more sensitive (than the data currently indicates) to reach the level of 

concern. Similarly, aquatic invertebrates would need to be 143 times more sensitive to reach the 

level of concern. Therefore, the Agency anticipates neither acute nor chronic risks to aquatic 

animals from d-limonene. There were no LOC exceedances for either aquatic vascular or aquatic 

non-vascular plants. 

Endangered Species Assessment 

In November 2013, the EPA, along with the U.S. Fish & Wildlife Service (USFWS), the 

National Marine Fisheries Service (NMFS) (collectively, the Services), and the U.S. Department 

of Agriculture (USDA) released a summary of their joint Interim Approaches for assessing risks 

to listed species from pesticides. The Interim Approaches were developed jointly by the agencies 

in response to the National Academy of Sciences' (NAS) recommendations and reflect a 

2 (I] 

http://www2.epa.gov/sites/production/files/201406/documents/pollinator risk assessment guidance 06 19 14.pdf 

8 
common approach to risk assessment shared by the agencies as a way of addressing scientific 

differences between the EPA and the Services. The summary outlines recommendations on 

specific scientific and technical issues related to the development of pesticide risk assessments 

that EPA and the Services must conduct in connection with their obligations under the 

Endangered Species Act (ESA) and FIFRA. 

The joint Interim Approaches were released prior to a stakeholder workshop held on 

November 15, 2013. In addition, the EPA presented the joint Interim Approaches at the 

December 2013 Pesticide Program Dialogue Committee (PPDC) and State-FIFRA Issues 

Research and Evaluation Group (SFIREG) meetings, and held a stakeholder workshop in April 

2014, allowing additional opportunities for stakeholders to comment on the Interim Approaches. 

As part of a phased, iterative process for developing the Interim Approaches, the agencies will 

also consider public comments on the Interim Approaches in connection with the development of 

upcoming Registration Review decisions. The details of the joint Interim Approaches are 

contained in the white paper "Interim Approaches for National-Level Pesticide Endangered 

Species Act Assessments Based on the Recommendations of the National Academy of Sciences 

April 2013 Report," dated November 1, 2013. 

Given that the agencies are continuing to develop and work toward implementation of the 

Interim Approaches to assess the potential risks of pesticides to listed species and their 

designated critical habitat, the ecological risk assessment supporting this d-Limonene Proposed 

Interim Registration Review Decision does not contain a complete ESA analysis that includes 

effects determinations for specific listed species or designated critical habitat. Although EPA has 

not yet completed effects determinations for specific species or habitats, for this preliminary 

assessment EPA conducted a screening-level assessment for all taxa of non-target wildlife and 

plants that assumes for the sake of the assessment that listed species and designated critical 

habitats may be present in the vicinity of the application of d-limonene. This screening level 

assessment will allow EPA to focus its future evaluations on the types of species where the 

potential for effects exists once the scientific methods being developed by the agencies have 

been fully vetted. While the agencies continue to develop a common method for ESA analysis, 

the regulatory section of the proposed interim registration review decision document will 

describe the level of ESA analysis completed for this particular registration review case. Once 

the agencies have fully developed and implemented the scientific methods necessary to complete 

risk assessments for endangered and threatened (listed) species and their designated critical 

habitats, these methods will be applied to subsequent analyses for d-limonene as part of 

completing its registration review. 

Ecological Incidents 

Reviews of the Ecological Incident Information System (EIIS) and the Avian Incident 

Monitoring System (AIMS) were conducted on September 9, 2014. There are no reported 

incidents for d-limonene in the EIIS or AIMS databases. In addition to a review of the EIIS and 

AIMS databases, the Agency also reviewed the Aggregate Incidents Data Base. A single incident 

9 
associated with d-limonene was found, which was described as 'minor plant' damage. No further 

information is available. 

C. Endocrine Disruptor 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 most recent registration decision for d-limonene, 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 ), dlimonene 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 tq 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. A second list of 

chemicals identified for EDSP screening was published on June 14, 20133 and includes some 

pesticides scheduled for Registration Review and chemicals found in water. For further 

information on the status of the EDSP, the policies and procedures, the lists of chemicals, future 

lists, the test guidelines and the Tier 1 screening battery, please visit our website. 4 

In this interim decision, EPA is making no human health or environmental safety findings 

associated with the EDSP screening of d-limonene. Before completing this Registration Review, 

the Agency will make an EDSP FFDCA section 408(p) determination. 

3 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of 

chemicals. 4 http://www.epa.gov/endo/ 

10 
III. Risk Characterization and Proposed Interim Registration Review 

Decision 

A. Risk Characterization 

Through its ecological risk analysis, the Agency identified LOC exceedances for 

mammals from exposure to d-limonene and slight LOC exceedances to certain plants at the edgeof-field. However, as these RQs are based on screening level estimates, they reflect a number of 

inputs, assumptions, and judgments with respect to both the hazard and exposure of d-limonene. 

To better understand an estimate of potential risk, the Agency can characterize it by employing 

alternative assumptions (regarding either the hazard or exposure) which leads to alternative risk 

estimates and a broader understanding of potential risk. With respect to d-limonene risk to 

mammals, the Agency further explored its assumptions regarding exposure (both the foliar halflife of d-limonene, and the resulting duration of effect), and hazard (both the acute and chronic 

toxicity endpoints used). 

The Agency lacks chemical-specific foliar half-life data for d-limonene, and therefore 

assumed a 35-day half-life. However, based upon the volatility of d-limonene (information 

provided by the technical registrant) and magnitude of residue data, the Agency estimated that 

the foliar half-life of d-limonene may be much lower than 35 days, and may actually range 

between 3 and 15 hours. If the Agency uses a foliar half life of 48 hours, then the acute 

mammalian RQs drop from <LOC - 7.98 to <LOC - 1.6, and the chronic mammalian RQs drop 

from <LOC - 140.37 to <LOC - 28. Further, if a 48-hour foliar half-life is assumed, terrestrial 

exposure modeling predicts environmental exposure levels (i.e., those that lead to LOC 

exceedances) would only persist for 1-2 days following application; indicating that estimated risk 

would be of a limited duration. 

With respect to the toxicity endpoints, the endpoint used to estimate acute mammalian 

RQs was based on the lower of the two LDso values available from the same study with rat [(i.e., 

4400 mg/kg-bw (d'), and 5100 mg/kg-bw )]. If the Agency uses the higher acute endpoint 

(5100 mg/kg-bw) then the acute RQs would be reduced. The endpoint used to estimate chronic 

mammalian RQs (NOAEC = 250 mg/kg/day) was based upon a LOAEC of 500 mg/kg/day. The 

Agency notes that the LOAEC of 500 mg/kg/day was associated with small reductions in 

maternal body weight, which may not impact either the growth, reproduction or survival of the 

organism, and therefore may be considered a slight biological effect. If the Agency uses the 

LOAEC of 500 mg/kg-bw where slight effects occur then the chronic RQs are also reduced. 

When the characterizations of both the exposure ~nd hazard of d-limonene are considered 

together, the Agency believes that risk to mammals is not considered high at the lower 

application rates (i.e., 4.6 lbs. a.i./ A and 18.4 lbs. a.i./ A). Additionally at the higher application 

rates, (i.e., 34.6 lbs. a.i./ A and 55 .2 lbs. a.i./ A) potential risks are likely lower than estimated in 

the screening level analysis, and not likely to be persistent under environmentally relevant 

conditions. 

As noted above, the Agency does not have data to estimate potential risk of d-limonene to 

terrestrial invertebrates, but intends to require these data, consistent with the June 2014 Guidance 

11 
for Assessing Pesticide Risks to Bees5

. The Agency is currently evaluating an effort to require 

pollinator data for chemicals in registration review whose docket opened prior to June 2014. For 

those chemicals, the Agency intends to issue a DCI for all pollinator data in order to assess 

potential risk to pollinators. In the near future, EPA will provide information and guidance on 

this effort. The pollinator studies that will be required under this effort are listed in Table 1. 

Table 1. Anticipated Pollinator Data Requirements 

Guideline# Study 

850.3020 Honey bee adult acute contact toxicity 

850.3030 Honey bee toxicity of residues on foliage 

850.3040 Full-Field testing for pollinators 

Non-Guideline (OECD 213) Honey bee adult acute oral toxicity 

Non-Guideline (OECD 237) Honey bee larvae acute oral toxicity 

Non-Guideline Honey bee adult chronic oral toxicity 

Non-Guideline Honey bee larvae chronic oral toxicity 

Non-Guideline Field trial of residues in pollen and nectar 

Non-Guideline (OECD 75) Semi-field testing for pollinators 

With respect to potential risk to domestic animals, the Agency conducted a review of its 

Aggregate Incident Database System (IDS) for domestic animal incidents associated with dlimonene products between January 2010 to July 2015 (S.Recore, Aug 2015). The review 

indicated 231 incidents that involved domestic pets and products that contained d-limonene, and 

that not all incidents involved a pet care product but included other d-limonene products used in 

residential settings. The Agency's report indicated that the majority (71 %) of incidents were 

classified as minor (animal having minimal, rapidly-resolving symptoms), and that 10% were 

classified as either severe or fatal. The Agency's review also indicated that of the incidents 

involving a pet, the d-limonene pet product implicated in the majority (82%) of these incidents 

was a pet shampoo product (EPA registration no. 2724-759). Based upon EPA reporting 

requirements, information on domestic animals is submitted to the Agency as aggregate 

accounts, and as a consequence reports often lack narrative details on an incident, e.g., the 

species, gender, route of exposure or other information that may indicate potential misuse of the 

product. Therefore, to obtain insight on the incidents involving this product, the Agency 

contacted the technical registrant. 

The Agency sought sales and additional incident information from the technical 

registrant, Wellmark International. This information indicated unintended exposures (e.g., 

ocular, or dietary exposure) and or inappropriate use (e.g., leaving the product on the animal for 

too long) comprised 43% of the events associated with product no. 2724-759. Further, if the 

number of incidents associated with product no. 2724-759 is viewed in light of sales data, then a 

low incident rate, (0.02%) is revealed, or 1 incident per 5,000 units sold. If you consider that 

each unit is likely used multiple times, the incident rate would decrease even further. Based on 

these considerations, the Agency believes that while direct application of a pesticidal product 

5 http://www2.epa.gov/sites/production/files/2014-

06/documents/pollinator risk assessment guidance 06 19 14.pdf 

12 
presents potential inherent risk, it does not believe that the frequency or severity of risk from pet 

product(s) with d-limonene is unreasonable. However, to increase the safety surrounding the use 

of this pesticidal pet product, the Agency and W ellmark International identified additional label 

language for EPA registration 2724-759, Holiday Flea and Tick Shampoo for Dogs, Cats, 

Puppies, and Kittens as described in Section III. D. 

B. Benefits 

The Agency believes that the availability of d-limonene products may be a valuable 

alternative for certain pesticide users. As noted above, d-limonene is a naturally occurring 

compound with a wide range of uses and may be used in organic production. While it is a dermal 

sensitizer, it is known to have low toxicity and is Generally Regarded as Safe (GRAS) by the 

U.S. Food and Drug Administration for some uses. Because of these characteristics, the 

availability of d-limonene among other conventional pesticide products may be considered a 

benefit. 

C. Proposed Mitigation 

While the Agency believes that the risk to mammals and domestic pets from d-limonene 

is low, it nonetheless pursued measures to reduce potential risk from d-limonene products. To 

address potential risks to terrestrial mammals, terrestrial plants, and domestic pets, the Agency 

discussed mitigation options with the registrants of these products. 

Cutting Edge Formulations, and Orange Guard Inc. have agricultural products with the 

highest application rates. Cutting Edge has proposed to modify its product label (EPA 

registration 82052-4, Avenger Tm AG Burndown Herbicide) to limit the number of applications, 

currently not specified on the label and assumed to be 12, to two (2) applications per crop cycle. 

Orange Guard, Inc. has proposed to amend its product label (EPA registration 61887-3 Orange 

Guard Ornamental Plants Protection Concentrate) to indicate a higher dilution rate, from 1 :6 

(product to water) to 1 :8 (product to water). Both proposed changes will reduce overall 

environmental loading and therefore lower potential risk. W ellmark International, is the only 

registrant with an active domestic pet product and has proposed to modify their pet shampoo 

product (EPA registration 2724-759, Holiday Flea and Tick Shampoo for Dogs, Cats, Puppies, 

and Kittens) to indicate a minimum weight and age of a cat or dog to be treated with this product. 

D. Proposed Interim Registration Review Decision 

EPA has completed a quantitative ecological risk analysis, including a screening-level 

endangered species analysis, and has also completed a qualitative human health analysis of dlimonene. As part of the registration review, EPA has updated its database for this compound by 

requiring and receiving the following data. 

• GLN 850.4100: terrestrial plant toxicity (seedling emergence) 

• GLN 850.4150: terrestrial plant toxicity (vegetative vigor) 

• GLN 850.4400: aquatic plant toxicity 

• GLN 850.5400: algal toxicity 

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In accordance with 40 CFR Sections 155.56 and 155.58, the Agency is issuing this dlimonene Proposed Interim Registration Review Decision document. Except for the EDSP and 

ESA components of this case, the Agency is making the following Proposed Interim Registration 

Review Decision for d-limonene. 

• The Agency has not identified any human health risks of concern from the use of 

pesticide products that contain d-limonene. 

• With the exception of pollinator data, which the Agency anticipates requiring at a later 

date, no additional data needs have been identified for the registration review of dlimonene. 

• The Agency has identified LOC exceedances to terrestrial mammals and terrestrial plants, 

from the use of pesticide products that contain d-limonene. The Agency is proposing the 

following changes to certain d-limonene products (i.e., those with the highest application 

rates) that will reduce potential risk to terrestrial mammals and plants: 

• The Avenger Tm AG Burndown Herbicide label (EPA registration no. 82052-4) 

will specify the maximum number of applications as 2 per crop cycle. 

• The Orange Guard Ornamental Plants Protection Concentrate label (EPA 

registration no. 61887-3) will include an increased effective dilution rate of 1:8 

(from the current 1 :6). 

• To reduce potential risk surrounding pesticidal pet products that contain d-limonene, the 

Agency is proposing the following change to the product Holiday Flea and Tick 

Shampoo for Dogs, Cats, Puppies and Kittens, EPA registration no. 2724-759. 

• The Holiday Flea and Tick Shampoo for Dogs, Cats, Puppies and Kittens label 

(EPA registration no. 2724-759) will specify that the product cannot be used on 

dogs or cats that are younger than 6 months, or that weigh less than 5 pounds. 

Considering the conclusions of the screening-level risk analysis, the characterization of 

risks and exposure, as well as the benefits of d-limonene pesticide products, the Agency believes 

that with the adoption of these proposed risk mitigation measures, that potential risks to 

terrestrial mammals, plants and domestic pets would not be considered unreasonable. In this 

proposed interim registration review decision, EPA is making no human health or environmental 

safety findings associated with the EDSP screening of d-limonene, nor is it making a complete 

endangered species finding. The agency's final registration review decision for d-limonene will 

depend upon both the result of an ESA Section 7 consultation with the Services, and an EDSP 

FFDCA section 408(p) determination. 

IV. Next Steps and Timeline 

A. Interim Registration Review Decision 

A Federal Register Notice will announce the availability of this d-Limonene Proposed 

Interim Registration Review Decision in the d-limonene registration review docket, (EPA-HQOPP-2010-0673), accessible at www.regulations.gov, and allow a 60-day comment period. If 

there are no significant comments or additional information submitted to the docket during the 

comment period that leads the Agency to change its decision, EPA may issue an interim 

registration review decision for d-limonene (case 3083). However, a final decision fordlimonene may be issued without having previously issued an interim decision. A final decision 

14 
on the d-limonene registration review case will occur after an endangered species consultation 

with the services as well as an EDSP FFDCA section 408(p) determination has been made. A 

summary of the mitigation measures are described in Appendix A. 

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lAppendix A: Summary of Actions Taken for d-Limonene 

Registration Review Case#: 3083 

PC Code: 179701 

Chemical Type: Acaricide, insecticide, herbicide, and insect repellent. 

Chemical Family: Botanical 

Mode of Action: As an insecticide, the mode of action of d-limonene is believed to be by affecting the 

sensory nerves of the peripheral nervous system (not a cholinesterase inhibitor). As an herbicide, dlimonene is a non-systemic, contact herbicide that strips the waxy rind or cuticle from plants, causing 

death of the plant by desiccation. 

Affected Source of Route of Duration of Risk(s) of Concern Action(s) Taken Comment 

Population(s) Exposure Exposure Exposure (use to 

briefly 

clarify or 

elaborate 

on risk or 

mitigation) 

./ Mammals ,/ Direct ./ Dietary ./ 

./ Terrestrial application ./ 

Plants ,/ Spray drift 

./ Domestic and runoff 

pets 

Acute 

Chronic 

./ Acute 

mammalian 

RQs range 

from below 

the LOC to 8, 

and chronic 

mammalian 

RQs range 

from below 

LOC to 140 

./ Terrestrial 

plant RQs 

range from 

below the 

LOC to 

2.91(for 

listed plant 

species) 

./ Reproductive 

./ Desiccation 

./ Reduce 

application 

rate (from 

increased 

dilution 

rate) 

./ Reduce 

maximum 

number of 

applications 

./ Increase 

spray 

droplet size 

./ Label 

clarifications 

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Appendix B 

EPA Response to Comment by Center for Biological Diversity (CBD) 

CBD Comment: 

The Center for Biological Diversity (CBD) comment focus on EPA's independent duty under the 

Endangered Species Act (ESA) to consult with the U.S. Fish and Wildlife Service and the 

National Marine and Fisheries Service (Services) on the registration review of d-limonene. 

Specifically, CBD opposes the proposed decision for d-limonene prior to completion of 

consultation with the Services. 

EPA Response: 

Consistent with EPA's responsibility under the Endangered Species Act (ESA), the Agency will 

evaluate risks to federally listed threatened and endangered (listed) species from registered uses 

of pesticides in accordance with the Joint Interim Approaches developed to implement the 

recommendations of the April 2013 National Academy of Sciences (NAS) report, Assessing 

Risks to Endangered and Threatened Species from Pesticides. The NAS report outlines 

recommendations on specific scientific and technical issues related to the development of 

pesticide risk assessments that EPA and the Services must conduct in connection with their 

obligations under the ESA and FIFRA. EPA will address concerns specific to d-limonene in 

connection with the development of its final registration review decision for d-limonene. 

In November 2013 , EPA, the U.S. Fish and Wildlife Service, National Marine Fisheries 

(collectively, the Services), and USDA released a white paper containing a summary of their 

joint Interim Approaches for assessing risks to listed species from pesticides. These Interim 

Approaches were developed jointly by the agencies in response to the NAS recommendations, 

and reflect a common approach to risk assessment shared by the agencies as a way of addressing 

scientific differences between the EPA and the Services. Details of the joint Interim 

Approaches are contained in the November 1, 2013 white paper, Interim Approaches for 

National-Level Pesticide Endangered Species Act Assessments Based on the Recommendations 

of the National Academy of Sciences April 2013 Report. 

Given that the agencies are continuing to develop and work toward implementation of the 

Interim Approaches to assess the potential risks of pesticides to listed species and their 

designated critical habitat, the upcoming PID for d-limonene does not describe the specific ESA 

analysis, including effects determinations for specific listed species or designated critical habitat, 

to be conducted during registration review. While the agencies continue to develop a common 

method for ESA analysis, the planned PID for d-limonene will describe the level of ESA analysis 

completed for this particular registration review case. This PID will allow EPA to focus its future 

evaluations on the types of species where the potential for effects exists, once the scientific 

methods being developed by the agencies have been fully vetted. Once the agencies have fully 

developed and implemented the scientific methods necessary to complete risk assessments for 

listed species and their designated critical habitats, these methods will be applied to subsequent 

analyses of d-limonene as part of completing this registration review. 

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References: 

1. Registration Review - Problem Formulation for d-Limonene. Jim Goodyear and Silvia 

Termes. June 30, 2010. 

2. d-Limonene. Human-Health Assessment Scoping Document in Support of Registration 

Review. George F. Kramer, Allison Nowotarski, and Robert Mitkus. August 13, 2010. 

3. Limonene:Review of Human Incidents. Sarah Winfield, Shanna Recore and Khin Oo. May 

20, 2010. 

4. d-Limonene. Registration Review Response to Comment. Monique M. Perron. August 24, 

2015. 

5. Limonene and d-Limonene: Review of Domestic Animal Incidents. Shanna Recore. August 

25,2015. 

6. d-Limonene: P RD Response to Comments on Registration Review Preliminary Risk 

Assessment. Caitlin Newcamp. September 15, 2015. 

These and other supporting documents for the d-limonene registration review case may be found 

in the docket EPA-HQ-OPP-2010-0673 at http://www.regulations.gov 

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