Docket Number: EPA-HQ-OPP-2010-0673 www.regulations.gov



## d-Limonene Summary Document Registration Review: Initial Docket September 20103 of 14 

### TABLE OF CONTENTS

I. Preliminary Work Plan (PWP) 4

II. Fact Sheet 10

______________________ __________________

Please Note

This Preliminary Work Plan and Fact Sheet su mmarize the Environmental Protection Agency's current position based on the following documents:

1. Registration Review – Problem Formulation for d -Limonene. June 30, 2010

2. d-Limonene. Human-Health Assessment Scopi ng Document in Support of Registration Review. August 13, 2010

3. Limonene: Review of Human Incidents. May 20, 2010

4. Appendix A for Limonene. June 16, 2009

Supporting documents for Limonene may be found in the docket (EPA-HQ-OPP-2010-0673)

located on the internet at www.regulations.gov

.4 of 14 I. Preliminary Work Plan – d-Limonene

Introduction:

The Food Quality Protection Act of 1996 mandated a registration review program

. All pesticides

sold or distributed in the United Stat es (U.S) generally must be registered by the Environmental Protection Agency (EPA or the Agency), based on scientific data showing that they will not

cause unreasonable risks to human health or the environment when used as directed on product labeling. The registration review program is intende d to make sure that, as the ability to assess risk evolves and as policies and practices change, all registered pesticides continue to meet the statutory standard of no unreasonable adverse eff ects to human health or the environment. Changes in science, public policy, and pesticide use practices will occur over time. Through the registration review program, the Ag ency periodically reevaluates pest icides to make sure that as change occurs, products in the marketplace can be used safely. Information on this program is provided at: http://www.epa.gov/oppsrr d1/registration_review/

.

The Agency is implementing the registration revi ew program pursuant to Section 3(g) of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), a nd will review each registered pesticide every 15 years to determine whether it continues to meet th e FIFRA standard for registration. The Agency will consider benefits information and data as required by FIFRA. The public phase of registration review begins when the initial docket is opened for each case. The docket is the Agency’s opportunity to state what it knows about the pesticide and what additional risk analyses and data or information it belie ves are needed to make a registration review decision. After reviewing and responding to co mments and data received in the docket during this initial comment period, the Agency will de velop and commit to a final work plan and schedule for the registration review of d-Lim onene (“limonene” unless otherwise specified).

Limonene has a lemon-like flavor and smell, and occurs naturally in citrus and certain fruits, vegetables, meats, and spices. Limonene is us ed as both an active and inert ingredient in pesticide products, and as an ingredient in food products, soaps, and perfumes. Pesticide products containing limonene as an active ingredie nt are registered for use as insecticides, herbicides, insect repellents, and animal (dog and cat) repellents. As a pe sticide inert ingredient, it is used as a solvent or fragrance in an timicrobial products. The U.S. Food and Drug Administration (FDA) considers d-limonene to be Generally Recognized as Safe (GRAS) as a food additive when used as a synthetic flavor ing substance and adjuva nt (21 CFR §182.60).

Limonene is registered for use in/on terrestria l food, feed crops, non-food crops, for residential uses, and as an inert ingredient. Non-pesticid al uses of limonene include use in solvents (substitute for chlorinated hydrocarbons, chlorofl uorocarbons, and other solvents); use as a metal degreaser; use as a cleaning agen t in the printing industry and household cleaning products; and, as a solvent for paint. Limonene was first re gistered as an insecticide in 1958 and as an antimicrobial in 1971. Currently, the only antimi crobial uses of limonene are as an inert ingredient and are not subject for registration review. The re registration eligibility decision (RED) was issued in 1994 and th e tolerance reassessment eligibility decision (TRED) was issued

in 2005.5 of 14 Anticipated Risk Assessment and Data Needs:

The Agency anticipates conducting a comprehens ive ecological risk assessment, including an endangered species assessment, a new acute and chronic dietary assessment, an updated residential exposure and risk as sessment, an aggregate risk assessment (residential and dietary water), and an updated occupational exposure and ri sk assessment for all uses of limonene. A drinking water exposure and risk assessment is also anticipated in order to support registration review. Below is a summary of the issues rele vant to the registrati on review of limonene.

Ecological Risk:

• The most recent ecological risk assessment for limonene was completed in 1994 to support the RED.

• The Agency has not conducted a risk asse ssment that supports a complete endangered species determination for limonene. The ecological risk assessment planned during registration review will allow the Agency to determine whether limonene’s use has “no effect” or “may affect” federally listed threat ened or endangered sp ecies (listed species) or their designated critical ha bitats. When an assessment c oncludes that a pesticide’s use “may affect” a listed species or its designate d critical habitat, the Agency will consult with the U.S. Fish and Wildlife Service and/or National Marine Fisheries Service (the Services), as appropriate.

• Based upon the use pattern and limonene’s cu rrent ecotoxicity and environmental fate database, the Agency anticipates requiri ng the following data in order to conduct a complete ecological risk assessment, including an endangered species assessment, for all

uses:

o GLN 850.4100 - Seedling emergence, Tier II (using TEP)

o GLN 850.4150 - Vegetative vi gor, Tier II (using TEP)

o GLN 850.4400 - Aquatic plant toxicity test using Lemna spp. , Tier II (using TEP)

o GLN 850.5400 - Algal toxicit y, Tier II (using TEP)

• Please refer to the document, Registration Review – Problem Formulation for dLimonene dated June 30, 2010

, located in the docket for a detailed discussion of the anticipated risk assessment and data needs.

Human Health Risk:

• The most recent human health risk assessm ent for limonene was completed in 2004 to support the TRED.

• The RED DCI required a developmental toxic ity study and a 2-week dermal toxicity study. These studies have been received by the Agency and will be reviewed during registration review. The diet ary endpoints established in 2004 risk assessment may be updated following Agency review of these studies.6 of 14 • The human health toxicity database for limone ne is adequate to support its current use patterns and the Agency does not anticipate requiring new da ta to support a human health risk assessment for registration review.

• The Agency intends to conduct a new dietary ri sk assessment that in corporates potential drinking water residues a nd revised endpoints to s upport registration review.

• Limonene is listed in 40 CFR §180.539 without numeric toleran ces and is identified as being safe for use, as an insecticide, in ta blecloths and repellant strips and in food or feed-handling establishments. The Agency doe s not anticipate the need to re-evaluate this tolerance expression during registration review.

• The residential exposure assessment that wa s conducted to support the 2004 TRED only examined dermal exposure to pesticide products containing lim onene as an active ingredient. The Agency intends to update the 2004 residential assessment using the revised Agency Standard Operating Procedur es (SOPs) for residential exposure to incorporate potential changes in dermal and i nhalation endpoints, and to include exposure from outdoor uses and pet product uses.

• To support registration review, the Agency intends to conduct new and updated aggregate risk assessments once a dietary risk assessmen t incorporating drinki ng water residues and updated endpoints is available.

• The most recent occupational exposure and risk assessments for limonene were conducted in 2008 to support proposed new uses . The Agency intends to update the occupational exposure and risk assessment to include the inhalation route of exposure and potential changes in the hazard endpoints.

• Please refer to the document, d-Limonene: Human Health Assessment Scoping Document in Support of Registration Review dated August 13, 2010

, located in the

docket for a detailed discussion of the antic ipated risk assessment and data needs for

human health.

Other Anticipated Data Needs:

• GLN 830.7050 UV/Visible Light Ab sorption – this study is a new data requirement under 40 CFR part 158 (Product Chemistry Data Requi rements) for registration of a pesticide (food and non-food uses). The Agency antici pates requiring this study to obtain basic information about the compound’s identity/com position and the wavelengths at which the compound may be susceptible to photochemical degradation.7 of 14 Endocrine Disruptor Screening Program:

As required under FFDCA section 408(p), EP A has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (inc luding pesticide active and other ingredients) may have an effect in humans or wildlife si milar 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 ap proach to making the statutorily required

determinations. Tier 1 consists of a battery of 11 scr eening assays to identify the potential of a chemical substance to interact with the estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine related eff ects caused by the substance, and establish a quantitative relationship betw een the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticid e active ingredients and 9 inert ingredients.

This list of chemicals was selected based on th e potential for human exposure through pathways such as food and water, residen tial activity, and certain post-applic ation agricultural scenarios.

This list should not be construed as a lis t of known or likely endocrine disruptors.

Limonene was not among the group of 58 pesticide activ e ingredients or the 9 inerts on the initial

list to be screened under the EDSP. Under FFD CA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingly, EPA anticipat es issuing future EDSP orders/data call-ins for all Registration Review cases, in cluding those for which EPA ha s already opened a Registration Review docket for a pestic ide active ingredient.

For further information on the status of the ED SP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, pleas e visit our website: http://www.epa.gov/endo/

.8 of 14 Timeline:

EPA has created the following estimated timeline for the completion of the limonene registration

review.

Registration Review for Limonene – Pr ojected Registration Review Timeline

Activities Estimated Date Opening the Docket Open Docket and Public Co mment Period 2010 – September

Close Public Comment 2010 – November Case Development Final Work Plan 2011 – February

Issue DCI 2011 – Oct – Dec

Data Submission 2012 – Oct – Dec Open Public Comment Period for Preliminary Risk Assessments 2014 – April – June Close Public Comment Period 2014 – July – Sept Registration Review Decision Open Public Comment Period for Proposed Registration Review

Decision 2014 – Oct – Dec.

Close Public Comment Period 2015 – Jan. – March Final Registration Review Decision a nd Begin Post-Decision Follow-up 2015 Total (years) 5

Guidance for Commenters:

The public is invited to comme nt on EPA’s preliminary regist ration review work plan and rationale. The Agency will carefully consid er all comments as well as any additional information or data provided in a timely manner prior to issuing a final work plan for limonene.

Trade Irritants:

Through the registration review process, the Ag ency intends to solicit information on trade irritants and, to the extent feas ible, take steps toward facilitating irritant resolution. Growers and other stakeholders are asked to comment on any tr ade irritant issues resulting from lack of Maximum Residue Limits (MRLs) or disparitie s between U.S. tolerances and MRLs in key export markets, providing as much specificity as possible regarding the nature of the concern.

There are currently no establ ished Canadian, Codex, or Me xican MRLs for d-limonene,

harmonization is thus not an issue.

Water Quality:

Limonene is not identified as a cause of impairment for any wa ter bodies listed as impaired under section 303(d) of the Clean Water Act, based on information provided at http://iaspub.epa.gov/tmdl_waters10/attains_ nation_cy.cause_detail_303d?p_cause_group_id=88

5 . In addition, no Total Maximum Daily Loads (TMDL) have been developed for limonene,9 of 14 based on information provided at http://iaspub.epa.gov/tmdl_waters10/attains_ nation.tmdl_pollutant_de tail?p_pollutant_group_id =885&p_pollutant_group_name=PESTICIDES . More information on impaired water bodies and

TMDLs can be found at http://www.epa.gov/owow/tmdl/ . The Agency invites submission of water quality data for this pesticide. To the exte nt possible, data should conform to the quality standards in Appendix A of the OPP Standard Operating Procedur e: Inclusion of Impaired Water Body and Other Water Quality Data in OPP’s Regist ration Review Risk Assessment and Management Process (see: http://www.epa.gov/oppsrrd1/regist ration_review/water_quality_sop.htm ) in order to ensure they can be used quantitatively or qualitati vely in pesticide risk assessments.

Environmental Justice:

EPA seeks to achieve environmenta l justice, the fair tr eatment and meaningful involvement of all people, regardless of race, color, national origi n, or income, in the deve lopment, implementation, and enforcement of environmental laws, regulati ons, and policies. To help address potential environmental justice issues, the Agency seeks information on any groups or segments of the population who, as a result of thei r location, cultural practices, or other factors, may have atypical, unusually high exposure to limonene, compared to the general population. Please comment if you are aware of any sub-populatio ns that may have atypical, unusually high exposure compared to the general population.

Other Information:

Stakeholders are also specifically asked to prov ide information and data that will assist the Agency in refining the ecological and human h ealth risk assessments, including any speciesspecific ecological effects determinations. The Ag ency is interested in receiving the following

information:

1. suggestions from stakeholders on ways to reduce non-target organism exposures to

limonene

2. confirmation on the following label information:

a. maximum application rates in units rela ted to mass per unit area of treatment

zone b. geographic limitations on use

3. use or potential use distri bution (e.g., acreage and geogr aphical distribution of relevant crop)

4. use history

5. median and 90 th percentile reported use rates (lbs. a.i./acre) from usage data – national, state, and county

6. application timing (date of first applica tion and application intervals) by crop – national, state, and county

7. sub-county crop location data

8. directly acquired county-level usage da ta (not derived from state level data)

a. maximum reported use rate (lbs. a.i. /acre) from usage data – county10 of 14 b. percent crop treated – county

c. median and 90 th percentile number of applications – county

d. total pounds per year – county

e. the year the pesticide was last us ed in the county/sub-county area

f. the years in which the pesticide was applied in the county/sub-county area

9. state or local use restrictions

10. ecological incidents (non-target plant dama ge and avian, fish, reptilian, amphibian, and mammalian mortalities) not already reported to the Agency

11. monitoring data

Next Steps:

After the 60-day comment period closes, the Ag ency will review and respond to any comments received in a timely manner, and then issue its Final Work Plan (FWP) for the limonene registration review.11 of 14 II. FACT SHEET

Background Information :

• Limonene PC Code: 079701 CAS#: 5989-27-5

• Technical registrants:

o Wellmark International (EPA No. 2724)

o Cutting Edge Formulations, Inc. (EPA No. 82052)

o Florida Chemical Company, Inc. (EPA No. 82326)

• First registered for use in 1958.

• Reregistration Eligibility Decision issued in 1994 and the Tolerance Reassessment Eligibility Decision issued in 2005.

• There are 22 FIFRA section 3 registrations and no FIFRA section 24 (c) registrations.

• Pesticide Re-evaluation Divi sion Chemical Review Manager (CRM): Rusty Wasem wasem.russell@epa.gov

.

• Registration Division Co ntact: Jim Tompkins tompkins.jim@epa.gov (for herbicide products) Rita Kumar kumar.rita@epa.gov (for insecticide products) and Venus Eagle eagle.venus@epa.gov (for insecticide products).

Use & Usage Information: For additional details, please refer to the BE AD Appendix A document in the limonene docket.

• Limonene is used as both an active and inert ingredient in pesticid e products, and as a non-pesticidal ingredient in f ood products, soaps, and perfumes.

• Limonene is formulated as an emulsifiable concentrate, granul ar, liquid, pressurized liquid, and a read-to-use liquid.

• The Agency currently lacks data on the estimated nationwide use of limonene.

Recent Actions:

• New uses for limonene on tree, nut, vine, be rry crops, and non-crop areas were granted in March of 2008. An occupational risk assessm ent supporting this action can be found in

the limonene docket under the title d-Limonene Occupational Ex posure/Risk Assessment for Proposed New Uses of d-Limonene on Tr ee, Nut, Vine, Berry Crops and Non-Crop
Areas, dated February 25, 2008.

Ecological Risk Assessment Status : The following are key findings of the most recen t ecological risk assessments for limonene. Please refer to the document, Registration Review – Problem Formulation for d-Limonene

, located in the docket for a detailed discu ssion of the ecological risk assessment.

• Limonene is classified as pr actically non-toxic to most test species (avian and mammals) and only slightly toxic to other test orga nisms (freshwater fish and invertebrates).

• Previous risk assessments concluded that mini mal risk is anticipated for birds, mammals, and aquatic animals for the pesticidal uses of limonene. At the time of the 1994 RED, the12 of 14 Agency believed labeled applications of limonene did not pose risk to endangered species.

• Risk to terrestrial plants has not been quantified in previous assessments, and no terrestrial plant seedling emer gence or vegetative vigor to xicity data are currently available for limonene. Risk to aquatic plan ts has not been considered in previous assessments, and no aquatic vascular or non-va scular plant toxicity data are currently

available for limonene.

Human Health Risk Assessment Status: The following are key findings of the most recent human health risk assessments for limonene. Please refer to the document, d-Limonene. Human-Health Assessment Scoping Document in Support of Registration Review

, located in the docket for a de tailed discussion of the human

health risk assessment.

Hazard Characterization:

• Limonene has low acute oral and inhalation to xicity and moderate dermal toxicity. High doses ( ≥ 500 mg/kg/day) of limonene are needed to induce relevant toxicity in laboratory animals. It is a dermal irritant, a dermal sensitizer, and an eye irritant.

• Laboratory studies show no clear evid ence of limonene be ing a neurotoxin.

• Limonene has been classified as nega tive for carcinogenicity in humans.

Dietary (Food and Drinking Water):

• Screening level dietary exposure assessmen ts for limonene were conducted in 2004 to support the TRED. The assessments examined the potential dietary exposure (food only) to limonene as an inert ingredient in pest icide products. The exposure assessment, for limonene as an inert ingredient, incorporated extremely conservative assumptions, but did not include drinking water. Estimated dietary risks from this assessment were not of

concern.

Residential:

• The limonene TRED assessed residential de rmal risks from exposure to products containing limonene as an active ingredient for use scenarios registered at the time of the TRED. The only scenario that exceeded the Agency’s level of concern was the application of pet dips. The Agency considered this assessment to be an over-estimate of potential risk due to the conservative na ture of the hazard and exposure assessment.

Aggregate:

• The most recent aggregate risk assessments were performed for short- and long-term exposures to limonene in 2004 to suppor t the TRED. The 2004 aggregate risk assessment found short-term risks of concern, but these were considered to be an overestimate of potential risk due to the cons ervative nature of the hazard and exposure

assessment.

Occupational :13 of 14 • An occupational handler exposure/risk asse ssment was last conducted for proposed new uses of limonene on tree, nut, vine, berry cr ops, and non-crop areas in 2008. All of the occupational scenarios assessed were not of concern provided regist rants adopted label language requiring handlers we ar protective gloves.

• Past limonene risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, invo lving exposure to many different pesticides, comprise generic pesticide exposure database s such as the Pestic ide Handlers Exposure Database (PHED), the Outdoor Residential E xposure Task Force (ORETF) Database, and the Agricultural Reentry Task Force (ARTF) Database. EPA has reviewed all the studies supporting these multi-pesticide generic expos ure databases, and has found no clear and convincing evidence that the conduct of any of them was either f undamentally unethical or significantly deficient relative to the et hical standards prevailing at the time the

research was conducted. All a pplicable requirements of EPA’ s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to conti nued reliance on these studies.

Cumulative:

• The Agency has not determined whether limonene shares a common mechanism of toxicity with other chemical s ubstances. If, in the future, th e Agency determines that new

information on limonene is available that co uld potentially impact a cumulative risk assessment and result in a risk of concern, the Agency will revisit the need for a

cumulative risk assessment.

Incidents:

• The Office of Pesticide Programs Incident Data System (IDS) was reviewed for reports of limonene human incidents. Thirty-nine human incidents have been reported from 2002 to the present associated w ith the use of limonene. Of these cases, five involved limonene as a single chemical. The Center for Disease Control/National Institute for Occupational Safety and Health Sentinel Event Notification System for Occupational Risk-Pesticides (NIOSH) identif ied four human incidents invo lving the active ingredient limonene. Of these cases, one involved limonene as a single chemical (i.e. the product did not contain additional active ingredients) . Based on the low frequency and severity classification of the incident cases, there does no t appear to be a concern at this time that

would warrant furthe r investigation.

• No ecological incidents involving limonene were found in the Agency’s Ecological Incident Information System (EIIS) database.

Data Call-In (DCI) Status:

• DCIs were issued for limonene as part of th e reregistration process, and all previous data requirements have been satisfied.14 of 14 Tolerances and International Harmonization:

• Limonene is listed in 40 CFR §180.539 without numeric toleran ces and is identified as being safe for use, as an insecticide, in ta blecloths and repellant strips and in food or feed-handling establishments. Limonene is also listed among the inert ingredients for use in/on food commodities (40 CF R §180.910), and among the inert ingredient applied to animals (40 CFR §180.930), which are exempt from tolerances.

• Limonene is considered by U.S. Food and Drug Administration to be Generally Recognized as Safe (GRAS) (21 CFR §182.60) as a food additive.

• There are currently no establis hed Canadian, Codex, or Mexi can MRLs for d-limonene.

Harmonization is thus not an issue.

Labels :

• The labels for limonene can be obtained from the Pesticide Product Label System (PPLS)

website: http://oaspub.epa.gov/pestlabl/ppls.home

.