d-Limonene Registration -Review Human-Health Asse ssment Seeping Document

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF C HEMICAL SAFETY AND POL LUTION PREVENTION

MEMORANDUM

Date : 1 3-AUG-20 10

SUBJECT : d-Limonene. Human-Health Assessment Seoping Document in Support of Registration Review.

PC Codes: 079701 ,879701 Decision No .: 4283 46 Petition No .: N /A Risk Assessment Type : N /A TXR No .: N /A MRID No. : N / A DP Barcode: D37 4492 Registration No.: N /A Regulatory Action: Registration Review Seoping Document Case No .: 3083 CAS No.: 5989 -27 -5 40 CFR: §180.539

, §180 .910, §180.930



# - FROM: George F

. Kramer, Ph.D., Senior <)7rnist

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# <:5S:(

Allison Nowotarski, Biologist

### p. Robert Mitkus, Ph.D., DABT, Tox icologi s t Risk Assessment Brauch I (RAB I) 

## f::,. 

## ...5'

- 

## 0' Health Effects Division (HED, 7509P) "--- ---, - Office of Pesticide Programs (OPP)

THROUGH: Dana M. Vogel, Branch Chief RABI /HED/OPP (7509P)

TO: R u ssell Wa se m/Ni e l Anderson Pesticide Re-Evaluation Division (PRD)/OPP (7508P)

Attached is HED's human -health risk assessment scoping document for d-limonene to support Registration Review

.

Executive Summary

d -Limonene has a lemon -like flavor and sme ll, and occurs natura lly in citrus and certain fruits, vegetables

, meats, and spices. d -Limonene is used as both an active and inert ingredient in pesticide products

, and as an ingredient in food products

, soaps , and perfumes. As an active ingredient, it is used as an insecticide, herbicide

, insect repellent

, and animal (dog and cat) repellent. As a pesticide inert ingredient, it is used as a solvent or fragrance. FDA considers 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). d-Limonene is not registered for terrestrial food or feed crop uses as an act ive ingredient, but can be used in insect-repellent tab lecloths and in insect-repellent strips used in food or feed-handling establishments. Since the Pagelof31d-Limonene Registration-Review Human-Health Assessment Scoping Document



### Page 2 of 31 d-Limonene Tolerance Reassessment Eligibil ity Decision (TRED) was completed in 2004, a non-food herbicidal use has been as sessed and registered. No new food uses have been assessed or registered. The most recent human-health ri sk assessment for d-limonene was completed in 2004 (d-Limonene TRED, EPA-HQ-OPP-2004-0335-0003). HED has evaluated the status of the human-health assessments for d-limonene to de termine whether sufficient data are available and whether any updates are needed to support Re gistration Review. HED has considered the most recent human-health risk assessment for d-limonene (d-Limonene TRED, EPA-HQ-OPP2004-0335-0003); updates to its toxicity, exposure, a nd usage databases that have occurred since the last registration; and the most recently upda ted Agency science policy and risk assessment methodologies to determine the scope of work necessary to support Registration Review. No residue chemistry or toxicology data requirement s have been identified for d-limonene to support registration review

.

Background

The toxicology database is sufficient to support the current registrations. Overall, the database supports the conclusion that high doses of d-limonene ( ≥ 500 mg/kg/day) are needed to induce any form of relevant toxicity in laboratory animals. d-Limonene is a skin and eye irritant, as well as a dermal sensitizer, with ai r-oxidized (vs. unoxidized) d-limonene shown to be the sensitizing agent. d-Limonene is essentiall y non-toxic following single doses via the oral or dermal routes (LD 50 

### ≥ 4400 mg/kg) and inha lation routes (LC 50 

### >4.8 mg/L) and non-toxic in repeat-dose oral animal studies up to relatively high doses (500 mg/kg/day). In addition, a 2- week preliminary study for a 90-day dermal toxic ity study in the rat indi cated that d-limonene produced excessive dermal irritation at doses ≥ 500 mg/kg/day, but no system ic toxicity. Oral doses ≥ 75 mg/kg/day of d-limonene elicit effects in th e livers of rats; however, these effects are considered adaptive (non-adverse). The kidney was also identified as a ta rget organ in rodent toxicity studies, but only in ma le rats and not in any other sex or species. Extensive evaluation of the effects in the kidney of male rats determin ed that they are not pred ictive of kidney toxicity in humans. In addition, d-limonene was negative in several mutagenicity and clastogenicity assays. There was no evidence of developmenta l toxicity with d-limonene in rabbits and no evidence in rats, except at very high doses and in the presence of maternal toxicity. A clear noobserved adverse-effect level (NOAEL) of 250 mg/kg/day was obt ained for both maternal and developmental effects in rats. There was no evidence of possible neurotoxicity following exposure to d-limonene, except in a 13-week or al study in mice in which decreased motor activity was observed at a very high dose (1000 mg/kg/day); however, this observation could have been due to general systemic toxicity. A published 9-week immunotoxicity study in mice yielded no clear evidence of i mmunotoxicity with d-limonene.

In the Agency’s TRED (2004), EPA chose endpo ints for short- and long-term dermal and inhalation exposure scenarios, as well as chronic dietary exposure. The points of departure for the short- and long-term dermal and inhalati on exposure scenarios are considered overly conservative and inconsistent and should be updated in future ri sk assessments. In addition, based on expected exposure patterns, the need fo r acute dietary and inci dental oral toxicity endpoints should be addressed in future risk assessments as part of Registration Review.

The most recent chronic dietary-exposure asse ssment for d-limonene was completed in 2004 (dLimonene TRED, EPA-HQ-OPP- 2004-0335-0003). Screening-level assessments were performed using the Dietary E xposure Evaluation Model (DEEM TM 

### ) to determine the potential exposure for d-limonene in the food supply as a result of applications of a pesticide productd-Limonene Registration-Review Human-Health Assessment Scoping Document



### Page 3 of 31 containing d-limonene as an inert ingredient. Residues in drinking wate r were not included in the dietary risk assessments. For chronic diet ary risk assessments, a NOAEL of 150 mg/kg bw/d was selected, based on a 103-week oral gavage study in the male rat. For all populations addressed, the margins of exposure (MOEs) for d-limonene were greater than HED’s MOE of concern of 100; the most highly exposed subgroup was children (1-2 years old) with an MOE of 360. An acute assessment was not performed becau se no toxic effects attr ibutable to a single (i.e., acute) exposur e were identified.

The residue chemistry database is sufficient to support the current registrations. No new residue chemistry data requirements have been identified for d-limonene to support registration review.

There is sufficient information available to a ssess residential exposure. The residential assessment may need to be updated to incorpor ate any changes in short-term dermal and inhalation endpoints. Additionall y, handler inhalation exposure may also need to be assessed for the outdoor residential uses of lim onene. A revised residential a ssessment may also need to be performed to include residential handler dermal risks from use of pet shampoos and dips, as policies have recently changed. HED/OPP is currently revising the Residential Standard Operating Procedures (SOPs), including those us ed to determine exposure associated with pet treatments and impregnated bracel ets/clothing/pest strips . Residential exposure to d-limonene as an inert ingredient may also need to be re-a ssessed due to changes in methodologies since the 2004 TRED.

Because the indoor crack and crevice use of d-lim onene as an active ingredient is limited to inaccessible areas (applied under cabinets and behind appliances ) and because of its high volatility, post-applic ation residential dermal and incidental oral exposures are not expected for the indoor or outdoor residential uses. However, post-applicati on inhalation exposure may also need to be assessed for residential indoor and outdoor uses. Post-application dermal, inhalation, and hand-to-mouth exposure assessments for pe t shampoo and dip scenarios are recommended. Post-application exposure may also need to be assessed for impregnated clothing, bracelet, and strips uses that were not previ ously evaluated in the TRED. Re presentative residential handler scenarios and use sites are listed in Attachment 5.

The 2004 aggregate risk assessment found short-term risks of concern; however, the exposures are considered to be over-estimat ed due to (1) the volatile nature of d-limonene, (2) the overly conservative and inconsistent points of departur e for the short- and long-term dermal exposure scenarios, and (3) the conservati ve nature of the exposure assessment. A new acute and chronic aggregate risk assessment may also need to be conducted if a dietary risk assessment incorporating drinking water resi dues and updated endpoints is perfor med. Short-, intermediate-, and long-term aggregate risk estimates may also need to be updated once a revised residential assessment is available.

Occupational post-application expo sure to d-limonene has not been assessed. Because of the volatile nature of d-limonene (vap or pressure of 2 mm Hg), post- application dermal exposure is not expected. However, there is the potential for post-applicati on inhalation exposures from the use pattern and associated sites (i.e., applied as a spray at a high application rate). Postapplication inhalation exposure may also need to be assessed duri ng Registration Review.

There are currently no establis hed Codex or Mexican maximum residue limits (MRLs) for dlimonene. Harmonization is thus not an issue.d-Limonene Registration-Review Human-Health Assessment Scoping Document



### Page 4 of 31 Introduction

HED has evaluated the status of the human-health assessments fo r d-limonene to determine if sufficient data are available fo r Registration Review and whethe r any updates are required to support Registration Review. HED has considered the most recent human-health risk assessment for d-limonene (d-Limonene TRED, EPA-HQ- OPP-2004-0335-0003); updates to its toxicity, exposure, and usage databases that have occurr ed since the last regi stration; and the most recently updated Agency science policy and ri sk assessment methodologies to determine the scope of work necessary to support Registratio n Review. In addition, HED conducted an open search to look for new literature relevant to th e human-health risk assessment of d-limonene.

d-Limonene has a lemon-like flavor and smell, and occurs naturally in citrus and certain fruits, vegetables, meats, and spices. d-Limonene is used as both an active an d inert ingredient in pesticide products, and as an ingredient in f ood products, soaps, and perfumes. As an active ingredient, it is used as an in secticide, herbicide, insect re pellent, and animal (dog and cat) repellent. As a pesticide inert ingredient, it is used as a solvent or fragrance. FDA considers dlimonene to be GRAS as a food additive when used as a synthetic flavoring substance and adjuvant (21 CFR §182.60). d-Limonene is not registered for te rrestrial food or feed crop uses as an active ingredient, but can be us ed in insect-repellent tablecloths and in insect-repellent strips used in food or feed-handling establishments. Since the d-Limonene TRED was completed in 2004, a non-food herbicidal use has been assessed a nd registered. No new food uses have been assessed or registered. The most recent human-health risk assessment for d-limonene was completed in 2004 (d-Limonene TRED, EPA-HQ-OPP-2004-0335-0003).

The established tolerances and ex emptions, with the respective CF R citation, and the use patterns as an active and inert ingredie nt are listed in Table 1.

Table 1. Established Tolerances and Exemptions for d-Limonene.

Tolerance Exemption Expression CAS No. 40 CFR § PC Code Use Pattern List Classification

Active Ingredient

180.539 079701 Used in insect-repellenttablecloths and in insectrepellent strips used in food- or

feed-handling establishments NA

Inert Ingredient d-Limonene 5989-27-5

180.910 and 180.930 (formerly 180.1001(c) and (e)) a, b 879701 “Solvent, fragrance” 4B c

a Residues listed in 40 CFR §180.910 are exempt from a tolerance wh en used as inert ingredients in pesticide formulations appli ed to growing crops or to raw agricultural commodities after harvest and thos e listed in 40 CFR §180.930 are exempt from a tolerance when use d as inert ingredients in pesticide formul ations applied to animals.

b In both sections, the inert ingredient is listed as “d-Limonene (CAS Reg. No. 5989-27-5).”

c Inert ingredients are categorized into four lists as descri bed in the 1987 and 1989 Policy Statements. List 4B inert ingredi ents are those inerts for which EPA has sufficient information to reasonably conclude that the current use pattern in pesticide products will not adv ersely affect public health or the environment.



### Data needs and risk assessment updates required under registration review for d-limonene are as follows:

• Formal review of both the 1992 developmen tal toxicity study in rat (MRID 42316301) and the 1994 2-week dermal toxi city range finding study (MRID 43117001).d-Limonene Registration-Review Human-Health Assessment Scoping Document



### Page 5 of 31 • Reevaluation of endpoints fo r short- and long-term derm al and inhalation exposure scenarios, as well as chro nic dietary exposure.

• The need for acute dietary and incidental oral toxicity endpoints s hould be addressed as part of Registration Review.

• A new chronic dietary risk assessment in corporating drinking water residues and reevaluation of the dietary endpoints may be required. An acute dietary risk assessment also may be required.

• A new residential risk assessment may be required.

• A new occupational risk assessment may be required.

• A new aggregate risk assessment may also be required if revised di etary and residential exposure risk assessments have been performed.

Hazard Identification/Toxicology

d-Limonene has been evaluated extensively in a nu mber of short- and long- term toxicity assays since the 1950s. Overlapping su mmaries of these studies can be found in the EPA RED (1994) and TRED (2004), in reviews published by the World Health Organization (WHO; 1993, 1998), and in the technical report for d-limonene issued by the National T oxicology Program (NTP, 1990), which performed the carcinogenicity studies for d-limonene as well as several subchronic toxicity studies. The following hazard characte rization summarizes the toxicology of d-limonene that is described in these reports and assessmen ts, with additional information from the published literature where appropriate.

d-Limonene is a skin and eye ir ritant, as well as a dermal se nsitizer, with air-oxidized (vs. unoxidized) d-limonene shown to be the sensit izing agent (WHO, 1998). d-Limonene is essentially non-toxic following single doses via the oral or dermal routes (LD 50 

### ≥ 4400 mg/kg) and inhalation routes (LC 50 

### >4.8 mg/L) and non-toxic in repeat -dose oral animal studies up to relatively high doses (500 mg/kg/day). In a ddition, a 2-week preliminary study for a 90-day dermal toxicity study in the rat indicated that d-limonene produced excessive dermal irritation at doses ≥ 500 mg/kg/day, but no systemic toxicity. Oral doses ≥ 75 mg/kg/day of d-limonene elicit effects in the livers of rats; however, these e ffects are considered ad aptive (non-adverse) and were correctly identified as such in the EPA TRED, since they were limited to increased relative liver weights and/or liver enzy me induction in the absence of evidence of histopathology in the liver in short-term studies, lack of progre ssion to liver histopat hology with longer-term exposures and/or higher doses, and the absence of changes in clinical chemistry parameters in rodent studies that would be indicative of liver toxicity (summarized in TRED 2004). The changes in liver parameters are therefore consider ed to reflect the increased functional capacity of the liver to detoxify d-limonene. This interpretation is consistent with the 2002 HED guidance document on “Hepatocellular Hype rtrophy.” The only ev idence of possible hepatotoxicity in the database for d-limone ne was an increase (35%) in serum alkaline phosphatase and cholesterol and s lightly increased abso lute and relative liver weights in dogs treated orally with d-limonene for 6 months, as reported in WHO (1998). However, the findings were observed at a very high dose (1000 mg/kg/da y), and the increased serum cholesterol was contradicted by the observation of decreased choleste rol levels in an earlie r toxicity study in dogs at the same dose, as reported by NTP (1990), and decreased serum and liver cholesterol levels in rats exposed to d-limonene (WHO, 1993).d-Limonene Registration-Review Human-Health Assessment Scoping Document



### Page 6 of 31 The kidney was also identified as a target organ in rodent toxicity studies, but only in male rats and not in any other sex or species. Extensive evaluation of the effects in the kidney of male rats, which were characteristic of hyaline droplet nephropathy, le d to the conclusion by EPA, WHO, and NTP that the effects were associated with the increased pr oduction of the urinary protein, α 2u 

### -globulin, which is produced and excreted at high levels by the male rat only, and therefore not predictive of kidney toxicity in humans. This conclusion was supported by the observations that the concentration of d

- limonene was approximately 3 times higher in male rats than in female rats and approximately 40% was reversibly bound to α 2u 

### -globulin (WHO, 1998). Renal tubular cell tumors were also observed in male rats in the 2-ye ar carcinogenicity study performed with d-limonene. As was the case for the α 2u 

### -globulin nephropathy, the renal tumors were observed only in male rats, not in female rats, nor in mice of either sex in chronic bioassays. Several independent assessments determ ined that the kidney tumors observed in male rats do not pose a risk to humans, since they were observed only in animals with α 2u 

### -globulin nephropathy (a male rat-specific pheno menon) and humans do not synthesize α 2u 

### -globulin (WHO, 1998; Hard and Whysner, 1994; Whysne r and Williams, 1996). In addition, d-limonene was negative in several mutagenicity and clastogenicity assays.

WHO (1998) reported that there was no evidence of developmenta l toxicity with d-limonene, except at very high doses and in the presence of maternal toxicity. This conclusion was consistent with results from a developmental toxi city study in rats that was described in the 1994 RED and 2004 TRED. It was stated that an increased number of litters and fetuses with 14 th 

### rib (“extra rib”) was observed in this study at the same dose (500 mg/kg/day) as reduced body weight gain in maternal animals. A cl ear NOAEL of 250 mg/kg/da y was obtained for both maternal and developmental effects. This study should be formally reviewed for future regulatory actions for d-limonene. WHO (1998) a nd NTP (1990) also discussed the results of a developmental toxicity study in rabbits, in wh ich effects in dams, but not offspring, were observed at ≥ 500 m/kg/day. There was no evidence of possible neurotoxicity following exposure to d-limonene, except in a 13-week or al study in mice in which decreased motor activity was observed at a very high dose (1000 mg/kg/day) (WHO, 1998). However, as pointed out by WHO (1998), the effects may have been due to general systemic toxicity and not a neurotoxic effect at this high dos e. Mention was also made in WHO (1998) of a study in which various immune parameters were measured in mice exposed to d-limonene by gavage for 9 weeks (Evans, et al .; 1987). However, this study is of questionable reliability for several reasons, including (1) the doses to which the animals were exposedwere unreported, (2) there is a concern over the purity of the d-limonene that was teste d, and (3) effects were negative or equivocal. Overall, the database supports the conclu sion that high doses of d-limonene ( ≥ 500 mg/kg/day) are needed to induce any form of relevant toxicity in la boratory animals.

Orally administered d

- limonene is rapidly and almost co mpletely absorbed in humans and animals. d-Limonene is also well-absorbed vi a the dermal and inhala tion routes (WHO, 1998). The distribution (primarily to liver, kidney, and blood) and metabolism of d

- limonene is rapid; negligible amounts remain in the tissues of rats 48 hours after exposure. d-Limonene is metabolized primarily to the water-soluble metabolites, d

- limonene-8,9-diol a nd its glucuronic acid conjugate, as well as peri llic acid. Human and animal studies indicate that when administered orally, 75-95% of d-limonene is elim inated in the urine and <10% in feces within 2-3 days (NTP 1990).d-Limonene Registration-Review Human-Health Assessment Scoping Document



### Page 7 of 31 Endpoint Selection and Food Quality Pr otection Act (FQPA) Considerations

In the Agency’s TRED (2004), EPA chose endpo ints for short- and long-term dermal and inhalation exposure scenarios, as well as ch ronic dietary exposure. These endpoints are summarized in Attachment 2. The short-term dermal and inhalation endpoints were based on increases in liver weight and liv er enzymes (enzyme induction) in a 30-day short-term toxicity study in the rat. No adverse effects were observe d in any of the chronic studies. However, the highest dose tested from a 2-year chronic rat study (150 mg/kg/day) was used as a NOAEL and provided a highly conservative endpoint for the long-term risk assessment because there was no toxicity identified in this study. The points of departure for the short- and long-term dermal and inhalation exposure scenarios are considered over ly conservative and inconsistent and should be updated in future risk assessments for the follo wing reasons: 1) the short-term endpoint was based on adaptive (non-adverse) eff ects in the liver, 2) long-term and chronic risks were assessed based on a study with no identified toxicity, and 3) the extrapolated NOAEL for short-term exposures (400/3X=133.3) is lower than the NOAEL chosen for long-term exposures (150 mg/kg/day), thereby implying that the short-term toxicity of d-lim onene is greater than its longterm toxicity, which is unlikely. However, based on the lack of systemic toxicity at doses above the limit dose in a range-finding dermal toxicity study in rats, a dermal risk assessment may not be necessary in the future. In addition, based on expected exposure patterns, the need for acute dietary and incidental oral toxici ty endpoints should be addressed in future risk assessments as part of Registration Review. Currently, the study that provide s the smallest lowest-observed adverse-effect level (LOAEL)/NOAEL in the da tabase is a Good Laboratory Practice (GLP) developmental toxicity study in the rat that was submitted to the Agency in 1992 and summarized in both the RED (1994) and TRED (2004). It provides th e lowest point of departure that is not based on adaptive (non-a dverse) effects in the liver or ki dney effects in male rats only (which is an endpoint that is not relevant to humans). However, as noted above, the developmental toxicity study in the rat, as well as the range-finding dermal toxicity study, should first be formally reviewed by the Agency. The ma gnitude of the FQPA Safety Factor (SF) will also need to be determined in regulatory review and should reflect the low toxicity and lack of offspring susceptibility with d-limonene.

Endocrine Disruption

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 dose-response relationship between 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 pathwaysd-Limonene Registration-Review Human-Health Assessment Scoping Document



### Page 8 of 31 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.

d-Limonene was not among the group of 58 pesticide active ingredients on th e initial list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingly, EPA anticipates issuin g future EDSP test orders/data call-ins for all pesticide active ingredients.

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/.

Conclusions The toxicity database is adequa te to support existing registrations and regi stration review. dLimonene does not cause repeat-dose toxicity in laboratory animals except at high doses ( ≥ 500 mg/kg day), and there was no evidence of i mmunotoxicity in a pub lished immunotoxicity study with d-limonene. In addition, d-limonene occurs naturally in citrus frui ts and spices and is classified as GRAS by the F DA when used as a food additi ve. Therefore, although oral immunotoxicity, acute neurotoxicit y, subchronic neurotoxicity, and reproductive toxicity studies are now required, as specified in the most recen t 40 CFR Part 158 data requirements, the Agency does not believe that conducting these studies will provide any additional relevant information for human-health risk assessment.

A 90-day dermal toxicity study is not a requirem ent for food-use chemicals, as specified in 40 CFR Part 158. This study was onl y requested as “confirmatory” data in the 1994 RED. Due to the low toxicity of d-limonene vi a the oral route and the lack of systemic toxicity when tested up to 1500 mg/kg/day in a 2-week range-finding derm al toxicity study (summarized in the RED), systemic toxicity via the dermal route is not expected, except perhaps at doses above the limit dose. Therefore, HED does not believe that conducting a 90-day dermal toxicity study will provide additional relevant information for human- health risk assessment. In addition, a full 90- day dermal toxicity study may not be feasible , since mild to severe irritation, which was observed at the dose site at all doses tested in the 2-week rang e-finding dermal study in rats, may preclude a meaningful inte rpretation of the results.

The toxicity profile table for d-limonene, wh ich can be found in the 2004 TRED, should be updated to incorporate the results of an acute in halation toxicity study with d-limonene technical (LC 50 

### >4.8 mg/L, MRID 00150433). In addition, both the 1992 developmental toxicity study in rat (MRID 42316301) and the 1994 2-week derm al toxicity range finding study (MRID 43117001) should be formally reviewed by the Agency in order to verify the results of these studies, which have been summarized in the RED and/or TRED.

Residue Chemistry

No residue chemistry studies have been submitted or are required to support the currently registered food uses of d-limonene. HED notes that a study on the magnitude of residues resulting from foliar application of d-limonene to mustard greens has been submitted to the Agency (MRID# 47548301). Review of this study is not required to support the currently registered food uses of d-limonene.d-Limonene Registration-Review Human-Health Assessment Scoping Document



### Page 9 of 31 Conclusions The residue chemistry database is sufficient to support the current d-limonene registrations.

Dietary Exposure

The most recent chronic dietary-exposure asse ssment for d-limonene was completed in 2004 (dLimonene TRED, EPA-HQ-OPP- 2004-0335-0003). Screening-level assessments were performed to determine the potential exposure for d- limonene in the food supply as a result of applications of a pes ticide product containing d- limonene as an inert ingredient. This assessment would also cover any residues resulting from the d-limonene food uses (i.e., food additive and food-handling establishments). The following assumptions were used for the DEEM TM 

### modeling:

• Actual crop-specific residue data for active ingr edients can be utilized as surrogate data for inert ingredient residue levels (includi ng secondary residues in meat, milk, poultry and eggs);

• Inert ingredients are used on all crops; i.e ., 100% of all crops are “treated” with inert ingredients;

• No adjustment made for % of inert in formulation, application rate, or multiple applications of different ac tive ingredient formulations;

• Considers only preharvest applications.

For chronic dietary risk assessments, a NOAEL of 150 mg/kg bw/d was selected, based on a 103-week oral gavage study in the male rat. For all populations addressed, the MOEs for dlimonene were greater than the MOE of concer n of 100; the most highly exposed subgroup was children (1-2 years old) with an MOE of 360 (0.12 mg/kg body). By comparison, the intake of d-limonene from food sources for the general population was estimated to be 0.27 mg/kg body weight per day (Flavor and Ex tract Manufacturers Association (1991) d-Limonene Monograph). An acute assessment was not performed because no toxic effects attributable to a single (i.e., acute) exposure were identified.

d-Limonene is only somewhat soluble in water (13.8 mg/L) and has an es timated octanol/water partition coefficient of 4.2. d-Limonene is expe cted to rapidly volatili ze from water to the atmosphere, with an estimated half-life for volatilization from a m odel river of 3.4 hours, although adsorption to sediment and suspended or ganic matter may attenuate the rate of this process. Based on these data, it is unlikely that d-limonene will occur in drinking water sources resulting from any of the registered uses at the time the d-Limonene TRED was completed in 2004. Residues in drinking water were thus not incl uded in the dietary risk assessments. As new herbicidal uses of d-limonene with significantly higher use rates have been recently registered, actual estimated drinking water residues should be requested from the Environmental Fate and Effects Division (EFED) and, if fini te values are provided, incorporat ed in any future dietary risk

assessments.

Conclusions A new chronic dietary risk assessment incorpor ating drinking water residues and reevaluated endpoints may be required. An acute dietar y risk assessment also may be required.d-Limonene Registration-Review Human-Health Assessment Scoping Document



### Page 10 of 31 Residential Exposure

d-Limonene can be used as both an active and an in ert ingredient in products registered for use in residential environments. It is registered for use on many resident ial sites, including pets (as a shampoo or dip), outdoor premises (spot treatment ), indoor treatments (crack and crevice and cleaning uses), impregnated materi als (repellant clothing, bracelets, strips), roads and sidewalks (spot treatment), and professional applicati ons to wooden structur es (applied as a wood injection). Additional exposur e may occur naturally through different foods, soaps, and perfumes. These uses are FDA-approved and gene rally regarded as safe . The representative residential use patterns, applica tion rates and formulations of pe sticide products are provided in Attachment 5.

Residential Handlers HED has determined that residential handlers are likely to be exposed to d-limonene residues via dermal and inhalation routes during mixing, loadi ng, and application activities. HED expects the duration of the handler exposures to be short-term for the pet, the indoor crack and crevice, and outdoor residential uses, and long-term for the indoor cleaning uses of d-limonene. No handler exposure is expected to result from the wood injection treatment or repellant uses of d-limonene.

Based on anticipated used patterns and informa tion provided on the pr oduct labels, the TRED (2004) assessed residential dermal risks from e xposure to products containing d-limonene as an active ingredient (Table 5.1) examining the follo wing scenarios: loading/applying granulars by hand, mixing/loading/applying emulsifiable concentr ates with a watering can, applying ready-touse (RTU) formulations via pump-trigger spra y, applying RTU formulations via shampoo, and applying RTU formulations via dip. (An assess ment of handler inhalation exposure was not included in the TRED and, therefore, may need to be conducted during Registration Review). The only scenario which exceeded HED’s level of concern (MOEs were ≤ LOC = 300) was the application of pet dips (MOE = 81). HED is not concerned with risk esti mated in the TRED as the assessment is considered to be over-estimated due to the conservative nature of the hazard and exposure assessment. The pet handler asse ssment will be revisited during Registration Review to incorporate modificat ions in policy since the 2004 TRED , as well as potential changes is endpoint selection.

Residential handler dermal risk s from exposure to products cont aining d-limonene as an inert ingredient (Table 3.2) were also assessed in th e EPA TRED. Exposure was assumed to be from application of pressurized liqui d, RTU liquids, and emulsifiable and soluble concentrates. The EPA TRED assessed residential i nhalation exposure from long-t erm consumer use of general purpose cleaner and aerosol spra y (crack and crevice only) pr oducts (Table 3.3), which was assumed to represent the highest exposures expected for indoor us es. A revised assessment of residential handler inhalation e xposure is recommended for othe r exposure durations of indoor and outdoor residential use scen arios of products c ontaining d-limonene as an inert. The residential handler assessment ma y also need to be updated to in corporate potential changes in the hazard assessment, as well as changes in methodologies that have occurred since the 2004 TRED.

Residential Post-Application HED expects post-application dermal exposure to adults and children from the residential applications of d-limonene, with th e exception of the pet uses, to be negligible because of the use pattern and high volatility (2 mm Hg) of the chem ical. (Note: The EPA TRED did not examine post-application exposure). For the outdoor residential uses, chem ical residues are expected tod-Limonene Registration-Review Human-Health Assessment Scoping Document



### Page 11 of 31 quickly volatilize after applicati on and therefore are not expected to be available for contact. Additionally, because the indoor crack and crevice uses of limonene is limited to inaccessible areas (such as, under cabinets and be hind appliances), dermal and/or incidental oral exposure are not expected. However, due to the high vapor pr essure of limonene, there is the potential for post-application inhalation expos ure from both the indoor and outdoor uses of limonene. Postapplication inhalation exposure may need to be assessed for indoor and outdoor residential uses during the Registration Review process. Post -application dermal, inhalation, and hand-to-mouth exposures may need to be assessed for pet trea tment scenarios. Post-a pplication exposure may also need to be assessed for impregnated clot hing, bracelet, and strips uses that were not previously evaluated in the TRED.

Conclusion s There is sufficient information available to a ssess residential exposure. The residential assessment may need to be updated to incorporat e potential changes in s hort-term dermal and inhalation endpoints. Additionall y, handler inhalation exposure may also need to be assessed for the outdoor residential uses of lim onene. A revised residential a ssessment may also need to be performed to include residential handler dermal risks from use of pet shampoos and dips, as policies have recently changed. HED/OPP is curre ntly revising the Residential SOPs, including those used to determine exposure associat ed with pet treatments and impregnated bracelets/clothing/pest strips. Re sidential exposure to d-limonene as an inert ingredient may also need to be re-assessed due to changes in methodologies since the 2004 TRED.

Because the indoor crack and crevice use of d-lim onene as an active ingredient is limited to inaccessible areas (applied under cabinets and behind appliances ) and because of its high volatility, post-applic ation residential dermal and incidental oral exposures are not expected for the indoor or outdoor residential uses. However, post-applicati on inhalation exposure may need to be assessed for residential indoor and outdoor uses. A post-a pplication dermal, inhalation, and hand-to-mouth exposure assessments for pet sh ampoo and dip scenarios are recommended. Post-application exposure may also need to be assessed for impregnated clothing, bracelet, and strips uses that were not previ ously evaluated in the TRED. Re presentative residential handler scenarios and use sites are listed in Attachment 5.

Aggregate Risk Assessment

In the most recent human-health risk assessment (d-Limonene TRED 

### , EPA-HQ-OPP-2004-0335- 0003), aggregate risk assessments were performed for short- and long-term exposures. A cancer risk assessment was not conducted because d-limone ne has been classified as negative for carcinogenicity in humans and an acute assessmen t was not performed because no toxic effects attributable to a single (i.e., acu te) exposure were identified..

As the residential handler dermal risks from th e application of pet dips exceeded HED’s LOC, this scenario was not included in the aggregate ri sk assessment. To judge the potential aggregate exposures for d-limonene the Agency performed an aggregate assessment for two other residential scenarios: use in a cleaning product, and use in RTU pet shampoo formulations. The cleaning product represents the use of d-limonene as an inert ingredient in a product that could be used in and around the home. Cleaning products also tend to be used in a repetitive manner, and are more of a chronic type of scenario. The RTU pet shampoo form ulation represents the use of d-limonene as an active ingr edient in a product that could be used in and around the home.d-Limonene Registration-Review Human-Health Assessment Scoping Document



### Page 12 of 31 The RTU formulation also represents a very shor t-term scenario that could be measured in minutes that is of a non-repetitive nature.

Given that these two scenarios bracket the inert and active uses, as well as the short-term and more chronic types of scenarios, and that these two scenarios ha ve the lowest residential MOEs estimated for d-limonene, all other aggregate MO Es should be greater than the target MOE.

The short-term aggregate MOE is 290 (which combines dietary expos ure with residential exposure from the RTU pet shampoo formulations) and is less than the target MOE of 300. However, as previously discusse d, the dietary exposures are consid ered to be over-estimated due to the volatile nature of d-limonene. The driv er for the aggregate exposure is the residential exposure, which is also considered to be over- estimated. The long-term aggregate MOE (which combines dietary exposure with residential expos ure from the cleaning products) is 170 and is greater than the ta rget MOE of 100.

Conclusions The 2004 aggregate risk assessment found short-term risks of concern; however, the exposures are considered to be over-estimat ed due to (1) the volatile nature of d-limonene, (2) the overly conservative and inconsistent points of departur e for the short- and long-term dermal exposure scenarios, and (3) the conservati ve nature of the exposure assessment. To more realistically characterize risk, new acute and chronic aggregate risk assessments may need to be conducted once a dietary risk assessment incorporating drinking water residues a nd updated endpoints is available. Short-, intermediate-, and long-term aggregate risk estimates may also need to be updated once a revised residential assessment is available.

Occupational Exposure

d-Limonene is registered for use on tree, nut, vi ne, berry, vegetable, a nd flavoring/spice crops; and non-crop areas such as borders, driveways, sidewalks, patios, wood injection uses, and ornamental plants.

Occupational Handlers Occupational handler exposure is not assessed in the EPA TRED. An occupational handler exposure/risk assessment for proposed uses of d- limonene on tree, nut, vine, berry crops, and non-crop areas was conducted in February of 2008 (Memo, M. Dow, 2/25/08, D348549). Based on the use pattern, the most likely methods of app lication for tree, nut, vine, berry crops, and non-crop uses are by ground-boom spray machinery, lo w-pressure hand-wand sprayer, backpack sprayer, and hand-held pump-up sp rayer at a maximum application rate of 61.5 lbs ai/Acre. All assessed MOEs were not of concern to HED (MOEs were ≥ LOC = 100), provided handlers wear protective gloves. (It should be not ed that currently registered labels do not listed gloves as the required personal-protectiv e equipment (PPE)).

Occupational handler assessments have not been assessed for mixer/loader/applicators for wood protection treatments using injec tion equipment and package app licators; however, based on the label rate and use pattern, they are not expect ed to exceed HED’s LOC. In addition, a revised occupational handler assessment ma y be needed for the occupationa l use of aerosol cans. The assessment of occupational exposure and risk ma y also need to be updated based on potential changes to the hazard assessment.d-Limonene Registration-Review Human-Health Assessment Scoping Document



### Page 13 of 31 Occupational Post-Application Occupational post-application expo sure to d-limonene has not been assessed. Because of the volatile nature of d-limonene (vap or pressure of 2 mm Hg), post- application dermal exposure is not expected. However, there is the potential for post-applicati on inhalation exposures from the use pattern and associated sites (i.e., applied as a spray at a high application rate). Postapplication inhalation exposure may need to be assessed during Registration Review.

Conclusions There is sufficient information available to asse ss occupational handler exposure. There are occupational handler scenarios th at have not been assessed; ho wever, based on label rates and use patterns, they are not expected to exceed HED’s LOC. A post-application inhalation exposure assessment is recommended for i ndoor and outdoor uses. The assessment of occupational exposure and risk may also need to be updated based on potential changes to the hazard assessment. Representative occupational ha ndler scenarios and use sites are listed in Attachment 5.

Public Health and Pesticide Epidemiology Data

For this evaluation, both the O PP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System for Occupati onal Risk-Pesticides (SENSOR) database were consulted for pesticide incident data on the active ingredient d-limone ne. Additionally, the Agency is looking to include findings from the Agricultural Health Stud y (AHS), beginning with the problem formulation phase of registration review. The purpose of the database searches is to identify potential patterns on the ex tent and severity of the health effects attributed to d-limonene exposure. The IDS includes reports of alleged human-health incidents from various sources, including mandatory FIFRA Secti on 6 (a) (2) reports from regist rants, other federal and state health and environmental agencies, and indivi dual consumers. Since 1992, OPP has compiled these reports in IDS. IDS contains reports fr om across the U.S. and most incidents has all relevant product information recorded. Reports submitted to the IDS represent anecdotal reports or allegations only, unless otherwis e stated in the report. The NIOSH SENSOR database covers 12 states from 1998-2006, although repor ting varies from state to st ate (the database includes a total of 10,659 cases). Pesticide-related incide nts are collected from Department of Labor workers’ compensation claims when reported by physicians, reports from State Departments of Agriculture, from poison-control centers, and from State Departme nts of Health based on reports by physicians suspecting pesticide exposure. Although both occupational and non-occupational incidents are included in the da tabase, SENSOR focuses on occupa tional pesticide incidents, and is of particular value in providing that info rmation. A state SENSOR contact specialist does follow-up with workers and obtains medical re cords to verify symptoms, circumstances surrounding the exposure, severity, and outcome. Using standardized protocol and case definitions, derived from poison center reporting, SENSOR coordinators at State Departments of Health enter the incident interview descri ption provided by the wo rker, medical report, physician, and patient into the SENSOR data system , accessible to participating states and EPA. The AHS is a high-quality, prospective epidemio logy study evaluating the link between pesticide use and various health outcomes, including cance r. The AHS includes private and commercial pesticide applicators and their spouses. If there are AHS findi ngs relevant to a particular pesticide going through registration review, the Ag ency will ensure they are considered in the problem-formulation/scoping phase of the process and, if appropriate , fully reviewed in the risk-d-Limonene Registration-Review Human-Health Assessment Scoping Document



### Page 14 of 31 assessment phase of the process. The AHS in cludes information on the use of 50 different pesticide active ingredients comm only used in agriculture.

For IDS, HED identified 39 cases reported for d-l imonene in the United States from 2002 to the present. Of these cases, five were reviewed because in these cases d-limonene was used as a single chemical only and, theref ore, these cases provide more certain information about the potential effects of d-limonene exposure. Three of the cases appeared to involve exposure from using a flea and tick shampoo cont aining d-limonene in residential settings, and the remaining two cases involved postapplication exposure in residential settings (after professional application). The most frequently reported sy mptoms were neurological (38%), followed by dermal (25%); gastrointestinal , ocular, and miscellaneous symptoms were reported equally (13%). Proportions relate to th e total number of symptoms, not the total number of cases; i.e., an individual may report multiple symptoms to the database. See Attachment 7 for further details.

For NIOSH SENSOR, HED identified 4 cases repor ted that involve the active ingredient dlimonene. Of these cases, only one was reviewed b ecause, in this case, d-limonene was used as a single chemical only and had a certa inty classification of definite, probable, or possible. The case was an unknown age male who had a postapp lication exposure to d-limonene when he entered an office that had just been treated. He experienced ocular, resp iratory, neurological and gastrointestinal symptoms. This case was ranked low severity.

Limonene is not included in the AHS, and th erefore not considered in this report.

Based on the low frequency and severity of incide nt cases, there does not appear to be a concern at this time that would warrant further investig ation. Although there are in cidents reported that resulted in moderate outcomes, the symptoms and settings were vari ed and do not indicate a trend or pattern that would trigger follow-up anal yses. The Agency will c ontinue to monitor the incident information and if a con cern is triggered, additional analysis will be included in the risk

assessment.

Tolerance Assessment and International Harmonization

U.S. permanent tolerances (listed in 40 CFR §18 0.539) are summarized in Attachment 6. There are currently no establis hed Codex or Mexican MRLs for d-l imonene. Harmonization is thus not an issue.

Environmental Justice

Potential areas of environmental ju stice concerns, to the extent po ssible, were considered in the human-health risk assessment, in accordance w ith U.S. Executive Order 12898, “Federal Actions to Address Environmental Just ice in Minority Populations an d Low-Income Populations,” (http://www.hss.energy.gov/nuclearsafety/env/ guidance/justice/e o12898.pdf). The OPP typically considers the highest potential exposures from the le gal use of a pesticide when conducting human-health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diet s within the U.S., and people who may be exposed when harvesting crop s. Should these highest exposures indicate potential risks of concern, OPP further refines th e risk assessments to ensure that the risk estimates are based on the best available information.d-Limonene Registration-Review Human-Health Assessment Scoping Document



### Page 15 of 31 Human Studies

Past d-limonene risk assessments rely in pa rt on data from studies in which adult human subjects were intentionally exposed to a pest icide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as the Pesticide Handler s Exposure Database (PHED), the Outdoor Residential Exposure Task Force (ORETF) Database, and the Agricultural Reentry Task Force (ARTF) Da tabase. 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 fundame ntally unethical or significantly deficient relative to the ethical st andards prevailing at the time the research was conducted. All applicable requir ements of EPA’s Rule for the Protection of Hu man Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued reliance on these studies.

Data Requirements

Toxicology No toxicology data requirements have been id entified for d-limonene to support registration review.

Residue Chemistry No residue chemistry data requirements have been identified for d-limonene to support registration review.

Occupational and Residential Exposure No new occupational exposure or re sidential exposure data require ments have been identified for d-limonene to support registration review.

References

Table 2. Memoranda Relevant to Registration Review. Author Barcode Date Title

USEPA EPA-HQOPP-2004- 0335-0003 2003 Exposure and Risk Assessment on Lower Risk Pesticide Chemicals. d-Limonene.

USEPA EPA 738-R94-034. 1994 Reregistration Eligibility Decision (RED): Limonene.

Dow, M. D348549 25-FEB-2008 Occupational Exposure/Risk Assessment for Proposed New Uses of d-Limonene on Tree, Nut, Vine, Berry Crops and Non-Crop Areas. Winfield, S., et al. D374493 20-MAY-2010 Limonene: Review of Human Incidents.



### Evans DL, Miller DM, Jacobsen KL, Bush PB. 1987. Modulation of immune responses in mice by d-limonene. J. Toxicol. Environ. Health 20(1-2):51-66.

Flavor and Extract Manufacturer s Association (1991) d-Limonene Monograph. Washington, DC, pp. 1–4.d-Limonene Registration-Review Human-Health Assessment Scoping Document



### Page 16 of 31 Hard GC, Whysner J. 1994. Risk assessment of d-limonene: an example of male rat-specific renal tumorigens. Crit. Rev. Toxicol. 24(3):231-54.

National Toxicology Program (NTP). 1990. T oxicology and Carcinoge nesis Studies of dLimonene (CAS No. 5989-27-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies). NTP TR 347. U.S. Department of Health and Human Servi ces, Public Health Servi ce, National Institutes of Health. NIH Publication No. 90-2802.

Whysner J, Williams GM. 1996. d-Limonene mech anistic data and risk assessment: absolute species-specific cytotoxicity, enhanced cell pr oliferation, and tumor pr omotion. Pharmacol. Ther. 71(1-2):127-36.

World Health Organization (WHO). 1993. Toxico logical Evaluation of Certain Food Additives and Naturally Occurring Toxicants. Interna tional Programme on Chemical Safety. 39 th 

### Meeting of the Joint FAO/WHO Expert Committee on F ood Additives (JECFA). Accessed: 4/29/2010. Website: http://www.inchem.org/documents/jecfa/jecmono/v30je05.htm

World Health Organization (WHO). 1998. C oncise International Chemical Assessment Document No. 5: Limonene. International Progra mme on Chemical Safety. Prepared by: Dr. A. Falk Filipsson, National Institute for Working Life; Mr. J. Bard; Ms. S. Karlsson, National Chemicals Inspectorate. Accessed: 4/22/2010. Website: http://www.inchem.org/documents/cicads/cicads/cicad05.htm

Attachments

Attachment 1: Chemical Identity Table Attachment 2: d-Limonene Endpoint Selection Tables Attachment 3: Residential Use Patter ns/Exposure Scenarios for d-Limonene Attachment 4: Exposure Potential for A dult and Child Aggregate Risk Estimates Attachment 5: Occupational Use Patter ns/Exposure Scenarios for d-Limonene Attachment 6: d-Limonene International Residue Limit Status Attachment 7: IDS Report

cc: G. Kramer (RAB1), A. Nowotarski (RAB1), R. Mitkus (RAB1) RDI: RAB1 (5/19/10) G.F. Kramer:S10781:PY-S:(703)305-5079:7509P:RAB1d-Limonene Registration-Review Human-Health Assessment Scoping Document



### Page 17 of 31 Attachment 1: Chemical Identity Table

Chemical Identity of d-Limonene.

Structure

Molecular formula C 10 H 16 Molecular weight 136.2 g/mole Physical state colorless liquid, with characteristic mild citrus odor Melting point -75 ° ° C Boiling point 176 ° C Solubility in water 13.8 mg/L at 25 o C pH Not applicable Density/Specific Gravity 0.84 g/mL Vapor Density Relative vapor density = 4.7 (air = 1) Vapor Pressure 0.4 kPa at 14.4 o C; 2 mm Hg at 20 o C Estimated Octanol/Water Coefficient log Kow: 4.2 Dissociation Constant Not applicable References: NIOSH, 2001;

WHO, 1998d-Limonene Registration-Review Human-Health Assessment Scoping Document



### Page 18 of 31 Attachment 2: d-Limonene Endpoint Selection Table

Table 2. Summary of Toxicological Endpoints for Use in Human Risk Assessment – from the TRED (2004).

EXPOSURE SCENARIO DOSE (mg/kg/day) ENDPOINT STUDY

Short-Term Dermal and Inhalation LOAEL = 400 (only dose tested)

MOE = 300 increased relative liver weights and enzymes (nonadverse effects) 30-day rat oral (gavage) study [Ariyoshi, et al

. (1975) in WHO (1998)] Long-Term Dermal and Inhalation, and Chronic dietary NOAEL = 150 (highest dose tested)

MOE = 100 A LOAEL was not observed. 103-week oral gavage study in the male rat (NTP, 1990) NOAEL = no-observed adverse-effect level, LOAEL = lowest-observed adverse-effect level.DRAFT d-Limonene Registration Review Human-Health Assessment Scoping Document



### Page 19 of 31 Attachment 3: Previous Residential Assessment for d-Limonene (from d-Limonene TRED, EPA-HQ-OPP-2004-0335-0003)

Table 3.1. Residential Handler Risks Due to Ex posure to d-Limonene as an Active Ingredient.

Exposure Scenario Assumptions for estimating

product application rate Percent active ingredient Calculation of product application rate (AR) Application Rate Area Treated or Amount

Handled

Daily a Baseline Dermal MOE b

Loading/Applying Granulars by Hand From product label – apply 1 lb/800 ft 2 4 AR = (1 lb/800 ft 2 )*0.04 0.00005 lb ai/ft 2 1000 ft 2 /day 1,300

Mixing/loading/app lying emulsifiable concentrates with a watering can From product label, max application rate is 8 fl. oz and 5.6 lb ai/gallon 78.2 AR = 5.6 lb ai/gal *1 gal/128 oz * 8 oz/1000 ft 2 0.00035 lb ai/ft 2 1000 ft 2 /day 7,300

Applying RTU (Ready-to-Use) Formulations via

Pump-Trigger Spray Assume 0.125 gallons of product applied

per day and assume density

is 1.0 g/mL 5.8 AR = (1.0 g/mL * 0.0022 lb/g * 3785 mL/gal) * 0.058 0.48 lb ai/gallon 0.125 gal/day 2,100

Applying RTU Formulations via Shampoo Average size of shampoo bottle is 12 oz; use 1⁄2

bottle when shampooing pet; assume density

is 1.0 g/mL 5 AR = (1.0 g/mL * 1000mL/L * 1L/33.8 oz * 1000 mg/g * 6 oz/day) * 0.05 8,876 mg ai/day NA 320

Applying RTU Formulations via Dip From product label – use 1.5 oz/gallon of water; assume density is 1.0 g/mL 78.2 AR = (1.0 g/mL * 1000mL/L * 1L/33.8 oz * 1000 mg/g * 1.5 oz/day) * 0.782 34,704 mg ai/day NA 81

a Amount handled per day values are EPA estimates of amount treated based on revised Residential SOPs (2/01). b Baseline Dermal MOE = LOAEL (400 mg/kg/day) / dermal daily dose (mg/kg/day), where dermal dose = daily unit exposure (μg/lb ai) x application rate x amount handled per day x conversion factor (if needed) / body weight (70 kg adult). LOC = MOEs ≤ 300.DRAFT d-Limonene Registration Review Human-Health Assessment Scoping Document



### Page 20 of 31 LOC = MOEs ≤ 300. Table 3.2. Residential Handler Risks Due to Ex posure to d-Limonene as an Inert Ingredient.

Formulation Type Application method Crop Treated Application Rate Area treated or Amount Used Dermal MOE

Turf, Garden, Trees, Outdoor Perimeter Treatment 0.00023 lb/ft 2 1000 ft 2 170,000 Low-pressure

handwand Crack and Crevice 0.12 lb/gal 0.5 gal/day 660,000

Backpack Turf, Garden, Trees, Outdoor Perimeter Treatment 0.00023 lb/ft 2 1000 ft 2 3,300,000

Turf 20000 ft 2 28,000 Emulsifiable Concentrate

Hose-end

sprayer Garden and Trees 0.00023 lb/ft 2 1000 ft 2 550,000

Crack and Crevice 0.094 gal/day 56,000 Pressurized liquid Aerosol Outdoor paint and stain 0.28 gal/day NA 8,100 Turf and Garden 1.0 gal/day NA 2,300 Pump-trigger Crack and Crevice 0.50 gal/day NA 10,000

Paintbrush Trees and Outdoor Paint and Stains 1.0 gal/day NA 2,200

Airless

sprayer 15 gal/day NA 420

Backpack 5 gal/day NA 20,000 Outdoor Paint and Stains

5 gal/day NA 1,000 Low-pressure

handwand Crack and Crevice 0.50 gal/day NA 10,000 Pump-trigger 0.13 gal/day NA 18,000 RTU liquid

Low-pressure handwand Crack and Crevice 0.50 gal/day NA 10,000

Turf 410,000 Garden and Trees 120,000 Low-pressure

handwand Crack and Crevice 0.00023 lb/ft 2 1000 ft 2

490,000

Backpack Turf, Garden, Trees and Outdoor Perimeter Treatment 0.00023 lb/ft 2 1000 ft 2 2,400,000

Turf 20000 ft 2 21,000 Hose-end

sprayer Garden and Trees 0.00023 lb/ft 2 1000 ft 2 410,000

Crack and Crevice 0.12 lb/gal 0.5 gal/day 490,000 Soluble Concentrate

Low-pressure handwand Outdoor Perimeter Treatment 0.00023 lb/ft 2 1000 ft 2 120,000DRAFT d-Limonene Registration Review Human-Health Assessment Scoping Document



### Page 21 of 31 Table 3.3. Summary of Consumer Dermal and Inhalation Exposure.

Scenario a Weight Fractions Dermal Dose b (mg/kg-day) Dermal MOE c Inhalation Dose b (mg/kg-day) Inhalation MOE

General Purpose Cleaner 0.125 5.77e-02 2,600 7.53E-01 200 c Aerosol Spray Can 0.000734 NA e NA 3.22E-03 124,200 d

a This model run was developed using the Office of Pollution, Prevention, and Toxics (OPPT). The general purpose cleaner scenario was run with Standard New Chemicals Program assu mptions and defaults. The aerosol spray can scenario was modified to assess 60 days of use over a year. b Modeled for chronic dose rates. c MOE = NOAEL (150 mg/kg-day) / Average Daily Dose (mg/kg/day). d MOE = LOAEL (400 mg/kg-day) / Average Daily Dose (mg/kg/day). e NA = Not available. EFAST Consumer Exposure Module does not have a dermal exposure scenario for aerosol paint.DRAFT d-Limonene Registration Review Human-Health Assessment Scoping Document



### Page 22 of 31 Attachment 4: Exposure Potential for Adult and Child Aggregate Risk Estimates (from d-Limonene TRED, EPA-HQ-OPP-2004-0335-0003)

Dietary Risk Calculations

Estimated Chronic Dietary Exposure a and Risk b for a Generic Inert Ingredient. Population Subgroup c Estimated Exposure, mg/kg/day MOE U.S. Population (total) 0.120 1250 All infants (<1 year old) 0.245 610 Children (1-2 years old) 0.422 360 Children (3-5 years old) 0.310 480 Children (6-12 years old) 0.174 860 Youth (13-19 years old) 0.100 1500 Adults (20-49 years old) 0.087 1720 Adults (50+ years old) 0.086 1740 Females (13-49 years) 0.087 1720 a Exposure estimates are based on highest tolerance-level residues of high-use active ingredients for all food forms, including meat, milk, poultry, and eggs. b MOE = NOAEL (150 mg/kg/day) / Estimated Exposure (mg/kg/day). c Only representative population subgroups are shown.



### Short- and Long-Term Aggregate Risk Calculations

Aggregate MOEs.

Scenario Type of Assessment Exposure (dietary + residential) (mg/kg/day) MOE

RTU via shampoo short-term LOAEL = 400 mg/kg/day target MOE is 300 0.12 + 1.25 = 1.37 290

general cleaner long-term NOAEL = 150 mg/kg/day target MOE is 100 0.12 + 0.753 = 0.873 170DRAFT d-Limonene Registration Review Human-Health Assessment Scoping Document



### Page 23 of 31 Attachment 5: Occupationa l/Residential Use Patterns/Exposure Scenarios for d-Limonene

Table 5.1. Summary of Representa tive Use Patterns, Formulations, an d Application Rates for d-Limonene.

Use Site Scenario Covered? Max. Rate per App Max. Rate Unit/Area *UG Form Max. App Rate/ yr Application Equipment //Type

NON-FOOD/NON-FEED USES automobiles, taxis, limousines, recreational vehicles, & tires N 1 -- (L) *M1 PRL NS Aerosol can //Crack and crevice and/or spot treatment N .0663 lb/1 gal *O1 EC NS Not on label/ Sponge//Dip treatment/ Spongeon/ Sprinkle cats (adults/kittens)

N 1 -- (L) *O1 PRL RTU NS Aerosol can/ By hand/ Pump spray bottle //Animal treatment (spray)/ Shampoo Christmas tree plantations Y 1 part (L) *C1 L NS Hand held sprayer //Spray citrus Y 34.595 lb A EC NS Hooded sprayer //Broadcast commercial storages/warehouses premises N 1 -- (L) *C1 M1 PRL NS Aerosol can //Crack and crevice and/or spot treatment/ Injection treatment/ Outdoor general surface spray/ Perimeter

treatment commercial transportation facilities-nonfeed/nonfood N 1 -- (L) *M1 PRL NS Aerosol can //Crack and crevice and/or spot treatment N .1654 lb 1K sq.ft *M1 PRL NS Aerosol can //Crack and crevice

treatment commercial/institutional/ industrial premises/equip. (indoor) Y ( N for PRL) 1 -- (L) *M1 EC PRL NS Aerosol can/ Pressure

sprayer //Contact and/or surface treatment/ Crack and crevice and/or spot treatment/ Crack and crevice treatment/ Directed

spray Y ( N for PRL) 1 -- (L) *C1 EC PRL NS Aerosol can/ Pressure

sprayer //Contact and/or surface treatment/ Crack and crevice and/or spot treatment/ Crack and crevice treatment/ Directed spray/ Perimeter treatment (a) Y 1 part (L) *C1 EC NS Pressure sprayer //Mound drench (b) commercial/institutional/ industrial premises/equipment (outdoor)

N 10 sec location (L) *C1 PRL NS Aerosol can //Injection treatment/ Outdoor general surface spray (c)DRAFT d-Limonene Registration Review Human-Health Assessment Scoping Document



### Page 24 of 31 N .0663 lb/1 gal *O1 EC NS Not on label/ Sponge//Dip treatment/ Spongeon/ Sprinkle (a) dogs/canines (adults/puppies)

N 1 -- (L) *O1 PRL RTU NS Aerosol can/ By hand/ Pump spray bottle //Animal treatment (spray)/ Shampoo (b) forest trees (all or unspecified) Y 1 part (L) *J1 L NS Hand held sprayer //Spray (a) forest trees (softwoods, conifers) Y 1 part (L) *J1 L NS Hand held sprayer //Spray (a) grapes Y 34.595 lb A EC NS Hooded sprayer //Broadcast (a) Y 34.595 lb A EC NS Hooded sprayer //Broadcast (a) Y 1.2775 lb/1 gal *C1 EC NS Sprayer //Spray (b) greenhouses-in use

Y 1 -- (L) *C1 RTU NS RTU spray container //Spray (c) hospitals/medical institutions premises (human/veterinary) N .1654 lb 1K sq.ft *N1 PRL NS Aerosol can //Crack and crevice treatment (a) N 1 -- (L) *N1 PRL NS Aerosol can //Crack and crevice and/or spot treatment (b) N .1654 lb 1K sq.ft *O1 PRL NS Aerosol can //Crack and crevice treatment (a) household/domestic dwellings

Y ( N for PRL) 1 -- (L) *O1 EC PRL RTU NS Aerosol can/ Pressure sprayer/ RTU spray container //Aerosol fog or fumigation application/ Contact and/or surface treatment/ Crack and crevice and/or spot treatment/ Crack and crevice treatment/ Directed spray (b) N .1654 lb 1K sq.ft *O1 PRL NS Aerosol can //Crack and crevice treatment (a) household/domestic dwellings contents

N 1 -- (L) *O1 PRL NS Aerosol can //Crack and crevice and/or spot treatment (b) household/domestic dwellings indoor nonfood handling areas Y ( N for PRL) 1 -- (L) *O1 EC PRL NS Aerosol can/ Pressure

sprayer //Crack and crevice and/or spot treatment/ Directed spray (a) N .1654 lb 1K sq.ft *O1 PRL NS Aerosol can //Crack and crevice treatment (a) household/domestic dwellings indoor premises

N 1 -- (L) *O1 IMPR PRL RTU NS Aerosol can/ Im p regnated strip/ Sprayer //Crack and crevice and/orDRAFT d-Limonene Registration Review Human-Health Assessment Scoping Document



### Page 25 of 31 spot treatment/ Indoor general surface treatment/ Insecticidal strip treatment (b) Y .4015 lb 1K sq.ft *K1 G NS Not on label //Sprinkle (a) Y 1.2775 lb/1 gal *K1 EC NS Sprayer //Spray (b) Y ( N for PRL) 1 -- (L) *K1 EC IMPR PRL RTU NS Aerosol can/ Impregnated strip/ Pressure sprayer/ Pump spray bottle/ RTU spray container/ Sprayer //Contact and/or surface treatment/ Crack and crevice and/or spot treatment/ Crack and crevice treatment/ Directed spray/ Injection treatment/ Insecticidal strip treatment/ Outdoor general surface spray/ Perimeter treatment/ Spray (c) N 1 -- nest (L) *K1 PRL NS Aerosol can //Directed spray (d) Y 1 part (L) *K1 EC NS Pressure sprayer //Mound drench (e) N 10 sec location (L) *K1 PRL NS Aerosol can //Outdoor general surface spray (f) household/domestic dwellings outdoor premises

N 10 sec nest (L) *K1 PRL NS Aerosol can //Directed spray/ Outdoor treatment (g) human body/clothing while being worn N 1 -- (L) *O1 IMPR NS Ankle band/ Cloth/ Wrist band //Clothing treatment/ Skin contact treatment (a) manure Y 1 -- (L) *C1 RTU NS Pump spray bottle //Spray (a) Y 34.595 lb A EC NS Hooded sprayer //Broadcast (a) Y 1.2775 lb/1 gal *C1 EC NS Sprayer //Spray (b) Y ( N for PRL) 1 -- (L) *C1 EC PRL RTU NS Aerosol can/ Pressure sprayer/ Pump spray bottle/ RTU spray container //Directed spray/ Outdoor general surface spray/ Perimeter treatment/ Spray (c) nonagricultural outdoor buildings/structures

Y 1 part (L) *C1 EC NS Pressure sprayer //Mound drench (d) Y 1.2775 lb/1 gal *C2 EC NS Sprayer //Spray (a)nonagricultural rights-ofway/fencerows/hedgerows Y 1 -- (L) *C2 RTU NS RTU spray container //Spray (b) nonagricultural uncultivated areas/soils Y 34.595 lb A EC NS Hooded sprayer //Broadcast (a)DRAFT d-Limonene Registration Review Human-Health Assessment Scoping Document



### Page 26 of 31 Y .0894 lb/.5 gal *C1 EC NS Pump spray bottle //Soil treatment (b) Y 1.2775 lb/1 gal *C1 EC NS Sprayer //Spray (c) Y .3578 lb/2 gal *C1 EC NS Pump spray bottle //Soil drench treatment (d) Y 1 -- (L) *C1 RTU NS RTU spray container //Spray (e) nursery stock Y 34.595 lb A EC NS Hooded sprayer //Broadcast (a) Y 34.595 lb A EC NS Hooded sprayer //Broadcast (a) Y 1.2775 lb/1 gal *C2 EC NS Sprayer //Spray (b) Y 1 -- (L) *C2 RTU NS RTU spray container //Spray (c) Y 1 part (L) *C2 L NS Pump spray bottle //Spray (d) ornamental and/or shade

trees

Y 1 part (L) *C2 I1 EC L NS Hand held sprayer/ Pressure

sprayer //Mound drench/ Spray (e) Y 34.595 lb A EC NS Hooded sprayer //Broadcast (a) Y .4015 lb 1K sq.ft *C2 G NS Not on label //Sprinkle (b) Y 1.2775 lb/1 gal *C2 EC NS Sprayer //Spray (c) Y 1 -- (L) *C2 RTU NS RTU spray container //Spray (d) ornamental herbaceous plants

Y 1 part (L) *C2 M1 L NS Pump spray bottle //Spray (e) ornamental lawns and turf Y .4015 lb 1K sq.ft *C2 G NS Not on label //Sprinkle (a) Y 34.595 lb A EC NS Hooded sprayer //Broadcast (a) Y 1.2775 lb/1 gal *C2 EC NS Sprayer //Spray (b) Y 1 -- (L) *C2 RTU NS RTU spray container //Spray (c) Y 1 part (L) *C2 L NS Pump spray bottle //Spray (d) ornamental non-flowering plants

Y 1 part (L) *I1 L NS Hand held sprayer //Spray (e) Y 34.595 lb A EC NS Hooded sprayer //Broadcast (a) Y 1.2775 lb/1 gal *C2 EC NS Sprayer //Spray (b) Y 1 -- (L) *C2 RTU NS RTU spray container //Spray (c) Y 1 part (L) *C2 L NS Pump spray bottle //Spray (d) ornamental woody shrubs and vines

Y 1 part (L) *C2 I1 EC L NS Hand held sprayer/ Pressure

sprayer //Mound drench/ Spray (e) Y 1.2775 lb/1 gal *K1 EC NS Sprayer //Spray (a) paths/patios

Y 1 -- (L) RTU NS Pump spray bottle/DRAFT d-Limonene Registration Review Human-Health Assessment Scoping Document



### Page 27 of 31 *C2 RTU spray container //Outdoor general surface spray/ Spray (b) Y 34.595 lb A EC NS Hooded sprayer //Broadcast (a) Y .4015 lb 1K sq.ft *C2 G NS Not on label //Sprinkle (b) Y 1.2775 lb/1 gal *K1 EC NS Sprayer //Spray (c) paved areas (private roads/sidewalks)

Y 1 -- (L) *C2 K1 RTU NS Pump spray bottle/ RTU spray container //Outdoor general surface spray/ Spray (d) N .1654 lb 1K sq.ft *O1 PRL NS Aerosol can //Crack and crevice treatment (a) pet living/sleeping quarters

Y ( N for PRL) 1 -- (L) *O1 PRL RTU NS Aerosol can/ Pump spray bottle/ Sprayer //Animal bedding/litter treatment/ Crack and crevice and/or spot treatment/ Indoor general surface treatment (b) pome fruits Y 34.595 lb A EC NS Hooded sprayer //Broadcast (a) recreational areas Y ( N for PRL) 1 -- (L) *C1 PRL RTU NS Aerosol can/ Pump spray bottle //Injection treatment/ Outdoor general surface spray/ Perimeter treatment (a) refuse/solid waste containers (garbage cans) Y ( N for PRL) 1 -- (L) *K1 O1 PRL RTU NS Aerosol can/ Pump spray bottle/ Sprayer //Crack and crevice and/or spot treatment/ Outdoor general surface spray/ Spray (a) refuse/solid waste sites (outdoor) Y 1 -- (L) *C1 RTU NS Pump spray bottle //Outdoor general surface spray (a) sewage systems N 1 -- (L) *F1 PRL NS Aerosol can //Crack and crevice and/or spot treatment (a) ships and boats N 1 -- (L) *M1 PRL NS Aerosol can //Crack and crevice and/or spot treatment (a) small fruits Y 34.595 lb A EC NS Hooded sprayer //Broadcast (a) stone fruits Y 34.595 lb A EC NS Hooded sprayer //Broadcast (a) tree nuts Y 34.595 lb A EC NS Hooded sprayer //Broadcast (a) wide area/general indoor

treatment N 1 -- (L) *M1 PRL NS Aerosol can //Contact and/or surface treatment (a) wide area/general outdoor treatment (public health use) N 1 -- (L) *C1 PRL NS Aerosol can //Contact and/or surface treatment (a) wood protection treatment N 66.5 lb 1K sq.ft RTU NS Package applicatorDRAFT d-Limonene Registration Review Human-Health Assessment Scoping Document



### Page 28 of 31 *UG = Use group codes. *O1 //Wood surface treatment (a) N 1 -- (L) *O1 RTU NS Injection equipment //Void treatment (b) to buildings/products indoor

N 1 minute hole (L) *O1 RTU NS Injection equipment //Injection treatment (c)

N 66.5 lb 1K sq.ft *K2 RTU NS Package applicator //Wood surface treatment (a) N 1 -- (L) *K2 RTU NS Injection equipment //Void treatment (b) N 1 minute hole (L) *K2 RTU NS Injection equipment //Injection treatment (c) wood protection treatment to buildings/products outdoor

N 10 sec hole (L) *K2 PRL NS Aerosol can //Injection treatment (d) FOOD/FEED USES N .1654 lb 1K sq.ft *L2 PRL NS Aerosol can //Crack and crevice treatment (a) eating establishments

N 1 -- (L) *L2 PRL NS Aerosol can //Crack and crevice and/or spot treatment (b) egg packing plants (commercial) Y .1538 lb 1K sq.ft *L1 RTU NS Pump spray bottle //Crack and crevice treatment (a) N .1654 lb 1K sq.ft *L1 PRL NS Aerosol can //Crack and crevice treatment (a) food processing plant premises (nonfood contact)

N 1 -- (L) *L1 PRL NS Aerosol can //Crack and crevice and/or spot treatment (b) food stores/markets/supermarkets premises N 1 -- (L) *L1 PRL NS Aerosol can //Crack and crevice and/or spot treatment (a) food/grocery/marketing/ storage/distribution facility premise N 1 -- (L) *L1 PRL NS Aerosol can //Crack and crevice and/or spot treatment (a) N .1654 lb 1K sq.ft *L1 PRL NS Aerosol can //Crack and crevice treatment (a) household/domestic dwellings indoor food handling areas Y 1 -- (L) *L1 EC PRL NS Aerosol can/ Pressure

sprayer //Crack and crevice and/or spot treatment/ Directed spray (b) N .1654 lb 1K sq.ft*L1 PRL NS Aerosol can //Crack and crevice treatment (a) meat processing plant premises (nonfood contact)

N 1 -- (L) *L1 PRL NS Aerosol can //Crack and crevice and/or spot treatment (b) poultry processing plant premises (nonfood contact) N .1654 lb 1K sq.ft *L1 PRL NS Aerosol can //Crack and crevice treatment (a)DRAFT d-Limonene Registration Review Human-Health Assessment Scoping Document



### Page 29 of 31 (L) = The dosage information provided is from the label in terms of product (e.g., ounces, gallons, or pounds of product) because there was insufficient information (e.g., missing density, area, or a.i. percentages) to provide converted dosage information.

FORMULATION CODES EC : Emulsifiable Concentrate G : Granular IMPR : Impregnated Material L : Liquid PRL : Pressurized Liquid RTU : Liquid Ready-to-Use

USE GROUP CODES C1 : TERRESTRIAL NON-FOOD CROP C2 : TERRESTRIAL NO N-FOOD+OUTDOOR RESIDENTIAL F1 : AQUATIC NON-FOOD INDUSTRIAL I1 : GREENHOUSE NON-FOOD CROP J1 : FORESTRY K1 : OUTDOOR RESIDENTIAL K2 : OUTDOOR RESIDENTIAL + INDOOR RESIDENTIAL L1 : INDOOR FOOD L2 : INDOOR FOOD+INDOOR NON-FOOD M1 : INDOOR NON-FOOD N1 : INDOOR MEDICAL O1 : INDOOR RESIDENTIALDRAFT d-Limonene Registration Review Human-Health Assessment Scoping Document



### Page 30 of 31 Attachment 6: d-Limonene Int ernational Residue Limit Status

Summary of U.S. Tolerances and International MRLs. U.S. Canada Mexico 1 Codex Residue Definition: § 180.539 d-Limonene; tolerances for residues. (a) General. (1) The insecticide d-limonene may be safely used in insect-repellent tablecloths and in insect-repellent strips used in food- or feed-handling establishments.

(2) To assure safe use of the insect repellent, its label and labeling shall conform to that registered by the U.S. Environmental Protection Agency, and it shall be used in accordance with such label and labeling. None - None

Commodity Tolerance (ppm)/Maximum Residue Limit (mg/kg) Commodity U.S. Canada Mexico Codex None - None

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.DRAFT d-Limonene Registration Review Human-Health Assessment Scoping Document



### Page 31 of 31 Attachment 7: IDS Report

Chemical: Limonene Human Incidents

Incident Number Incident Date Product Name Registration Number City State Exposure Type* 018344 001 05-Jan-07 ADAMS FLEA & TICK SHAMPOO WITH D-LIMONENE 00475800141 LA HC Adult (18-64 year ol d without gloves on 3 s memory deficit, con fu difficulty expressing 018666 012 25-Jun-07 ADAMS FLEA & TICK SHAMPOO WITH D-LIMONENE 00475800141 NC HC Adult (18-64 year ol d dermally 3 days ago. top of her foot. She w were still there and n o ointment, and the sy m019670 002 29-Mar08 PRESCRIPTION TREATMENTBRAND PROCITRADLTM CONTACT 00049900497 GA HC Adult (18-64 year ol d her home; told her th a The next day she sta r vomiting and diarrhe a and developed vomit i abnormal liver functi stopped clotting, and gave the dog IV flui d dog died. 019849 002 25-Jun-08 PRESCRIPTION TREATMENTBRAND PROCITRADLTM CONTACT 00049900497 Anaheim CA HC A 73-year-old male w p rofessional extermi n p roduct. He develop e He went to his physi c symptoms got better.021325 020 20-Sep-09 ADAMS DLIMONENE FLEA & TICK SHAMPOO 00272400759 000270 AZ HC Adult (18-64 years o l forearms, and hands w next day he develope forearms. The dog w

* Severity Categories H Human H-A Human Fatality H-B Human Major H-C Human Moderate H-D Human Minor H-E Human Unspecified