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 ofActions 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 , identif y 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
.regula tions
.gov
. FIFRA, as amended by the Food Quality Protection Act (FQPA) of 1996, mandated the continuous review ofexisting 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 ofno 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 ofthe d

### limonene 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

3industrial and household uses. Currently, the only antimicrobial uses ofd-limonene are as an inert ingredient and are not subject to registration review.
The following list highlights significant events ofthe registration review ofd-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 ofd-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 ofthe 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 RiskAssessment for the Registration Review of d-limonene and the Registration Review Preliminary Human Health RiskAssessment 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. Ofthe 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 ofd-limonene. Specifically, CBD opposes the proposed decision for d-limonene prior to completion ofconsultation 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 ofthe concerns raised by CBD as part ofthe implementation plan for assessing the risks ofpesticides to listed species based on the recommendations ofthe April 2013 National Academy of Sciences (NAS ) report. EPA will address concerns specific to d-limonene in connection with the development ofits 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 ofpet 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 ofthe Incident Database System (IDS) for adverse events associated with domestic animals and pesticide products that contain d

### limonene. 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, ProposedInterim 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 Comment s on Registration Review Preliminary RiskAssessment , 

### 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 ofincidents since 2010 (M. Perron; Aug 2015). The Agency ' s report dated August 24, 2015 indicated 19 reported incidents ofminor severity, 3 ofwhich 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 ofLabor, State Departments of Agriculture and State Departments ofHealth) and is maintained by the Centers for Disease Control/National Institute for Occupational Safety and Health. Within SENSOR, 17 incidents were reported, 3 ofwhich were associated with respiratory effects. Therefore, based on its review ofcurrent data bases , the Agency believes that the low frequency and low severity ofhuman 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.



### 5Use and Usage
As an herbicide, d-limonene is a non-systemic, contact herbicide that strips the waxy rind or cuticle from plants causing death ofthe 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 ofthe 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 ofd-limonene for registration review. For a detailed discussion, see the d-Limonene Human Health RiskAssessment 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 ofits 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 ofd-limonene. Human health toxicity points ofdeparture have not been selected for any population subgroup, or for any route or duration ofpotential exposure for d-limonene. Therefore, based upon the low toxicity ofdlimonene, absence oftoxicity endpoints, and the classification ofd-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 ofd-limonene and absence oftoxicity 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. R omagni , F ranck E. Dayan 2000

. Natural products as sources for new mechani sms ofherbicidal action
. Crop Protection 19 (2000) 583

-589

. 6Aggregate 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 oflow frequency , oflow 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 ofthe Agency ' s environmental risk assessment for d-limonene is presented below. For detailed discussions ofall aspects ofthe environmental risk assessment, see the d-Limonene: Ecological RiskAssessment 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 ofdissipation for d-limonene is volatilization. Other dissipation processes include photodegradation in air, microbial-mediated aerobic soil metabolism, sorption to soil, and transport in runoffwater. Ecological Risk Characterization

7Terrestrial 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 ofdata. However, in June 2014, the Agency issued its Guidancefor Assessing Pesticide Risks to Bees2

, and the Agency has begun to require these data where applicable. In order to understand the potential risk ofd-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 ofAgriculture (USDA) released a summary oftheirjoint Interim Approaches for assessing risks to listed species from pesticides. The Interim Approaches were developedjointly 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 ofpesticide risk assessments that EPA and the Services must conduct in connection with their obligations under the Endangered Species Act (ESA) and FIFRA.
Thejoint 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 ofa 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 ofthe joint Interim Approaches are contained in the white paper " Interim Approaches for National-Level Pesticide Endangered Species Act Assessments Based on the Recommendations ofthe National Academy of Sciences April 2013 Report," dated November 1, 2013.
Given that the agencies are continuing to develop and work toward implementation ofthe Interim Approaches to assess the potential risks ofpesticides 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 ofnon-target wildlife and plants that assumes for the sake ofthe assessment that listed species and designated critical habitats may be present in the vicinity ofthe application ofd-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 ofthe proposed interim registration review decision document will describe the level ofESA 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 ofthe 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 ofthe EIIS and AIMS databases , the Agency also reviewed the Aggregate Incidents Data Base. A single incident

9associated 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 ofits 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 ofthe 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 ofa battery of 11 screening assays to identif y 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 ofthe EDSP where EPA will determine which, ifany, ofthe 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, 2013 3 and includes some pesticides scheduled for Registration Review and chemicals found in water. For further information on the status ofthe 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 ofd-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 , andjudgments with respect to both the hazard and exposure ofd-limonene. To better understand an estimate ofpotential 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 ofpotential risk. With respect to d-limonene risk to mammals, the Agency further explored its assumptions regarding exposure (both the foliar halflife ofd-limonene, and the resulting duration ofeffect), 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 ofd-limonene (information provided by the technical registrant) and magnitude ofresidue data, the Agency estimated that the foliar half-life ofd-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 of48 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 ofthe two LDsovalues 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 ofthe 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 ofboth the exposure**~nd** 

### hazard ofd-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



### 11for 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 ofresidues 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 ofresidues 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 ofits 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 %) ofincidents 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 ofthe incidents involving a pet, the d-limonene pet product implicated in the majority (82%) ofthese 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 ofthe 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% ofthe events associated with product no. 2724-759. Further, ifthe number ofincidents 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. Ifyou 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 ofa 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 ofrisk from pet product(s) with d-limonene is unreasonable. However, to increase the safety surrounding the use ofthis pesticidal pet product, the Agency and Wellmark International identified additional label language for EPA registration 2724-759, Holiday Flea and Tick Shampoofor Dogs, Cats, Puppies, and Kittens 

### as described in Section III. D.

B. Benefits


### The Agency believes that the availability ofd-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 ofuses 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 ofthese characteristics, the availability ofd-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 ofthese 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, AvengerTm 

### AG Burndown Herbicide) to limit the number ofapplications , 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. Wellmark 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 ofa 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 ofd

### limonene. As part ofthe 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

13In 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 ofthis case, the Agency is making the following Proposed Interim Registration Review Decision for d-limonene.
• The Agency has not identified any human health risks ofconcern from the use of pesticide products that contain d-limonene.
• With the exception ofpollinator 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 ofpesticide 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 AvengerTm 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 Shampoofor Dogs, Cats, Puppies and Kittens, EPA registration no. 2724-759.
• The Holiday Flea and Tick Shampoofor 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 ofthe screening-level risk analysis , the characterization of risks and exposure, as well as the benefits ofd-limonene pesticide products , the Agency believes that with the adoption ofthese 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 ofd-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 ofthis 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

14on 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 ofthe mitigation measures are described in Appendix A.

15lAppendix 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

16Appendix 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 ofd-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 ofpesticides in accordance with the Joint Interim Approaches developed to implement the recommendations ofthe April 2013 National Academy of Sciences (NAS) report, Assessing Risk s to Endangered and Threatened Speciesfrom 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 ofits 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 oftheir joint Interim Approaches for assessing risks to listed species from pesticides. These Interim Approaches were developedjointly 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 ofthe joint Interim Approaches are contained in the November 1, 2013 white paper, Interim Approaches for National-Level Pesticide Endangered Species ActAssessments 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 ofpesticides 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 ofESA 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 ofd-limonene as part ofcompleting this registration review.

17References:
1. Registration Review

- Problem Formulationfor 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: PRD 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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