UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 2046

OFFICE OF CHEM I CAL SAFETY AND POLLUT I ON PREVENT I ON

March 27,2011

MEMORANDUM

SUBJECT: Pine Oil : Human Health Risk Assessment Scoping Document in Support of Registration Review

PC Code(s): 067002 D P Barcode(s)/No(s) : 395374

Decision No .: 456733 Registration Numbers : Multiple

Petition No(s) .: NA Regulatory Action : Human Health Registration Review

Risk Assess Type: Single Chemical Case No(s)

. : 3113

TXRNo.:NA CAS No(s) : 8002-09-3

MRID No(s).: NA 40 CFR: None

FROM : Nathan Mottl, Biologist

## V~**~** Talia Lindheimer

, Chemist

Michelle Centra, Pharmacolog i st

Risk Assessment and Science Support Branch (RASSB)

Antimicrobials Division (751 OP)

TO: Rebecca von dem Hagen, Chemical Review Manager Regulatory Management Branch II

Antimicrobials Division (751 OP)

THRU: Timothy Leighton, Senior Scientist 

# «**~** I

Nader Elkassabany, Branch Chief 

## ---7**I~** Risk Assessment and Science Support Branch (RASSB)

Antimicrobials Division (751 OP)

Page 1 of29Page 2 of 29 EXECUTIVE SUMMARY

The Antimicrobials Division (AD) Registrati on Review Team has evaluated the status of the human health assessments for pine oil (Reregistration Review case 3113 and PC code 067002) (D395481 and D395482). The first pine oil registration was issued in December, 1947. A Reregistration Eligibilit y Decision (RED) document was issued for pine oil in 2006 (USEPA, 2006a). Toxicologi cal end-points were identified, and a human health assessment (dietary, residential and occupational) was conducted for the RED. New toxicity and exposure study data have not b een received since issuance of the RED. The Agency anticipates reviewing any data receive d in response to the RED as well as data requested in this registration review pr ior to conducting the registration review assessments for pine oil.

The purpose of this document is to determin e whether sufficient data are available to support registration review, report on whether past risk assessments are still applicable and adequate and to report whethe r new human health assessments are needed to support the registration review process. T oxicological end-points were identified, and a human health assessment (dietary, residentia l and occupational) was conduct ed during the reregistration

process.

Currently there are 57 active pine oil registrations (6 t echnical products) registered under Section 3 of the Federal Insecticide, F ungicide, and Rodenticide Act (FIFRA). Pine Oil (1-Methyl-4-isopropyl-1-cyclo-hexen-8-ol) is approved for use as an antimicrobial sanitizer, fungicide, mildewstat, deo dorizer, disinfectant, virucide, and

microbicide/microbistat to control animal pathogenic bacteria, ammonia producing bacteria, fungi, viruses and mold.

Pine oil-containing products include many use sites, such as eating establishments, food processing plants, commercial/institutio nal/industrial premises and equipment, household or domestic dwellings and contents, and medical sites. The active ingredient pine oil (PC Code 067002) is a mixture of terpenes produced by high temperature distillation of oil of turpentine or by catalytic hydration of terpenes that forms a sole active ingredient containing no impurities. End use products are formulated as soluble concentrates, ready to use liquid solutions, and pressurized sprays.

Examples of some use sites where products containing pine oil may be used includes; but is not limited to : agricultural premises, food pro cessing facilities, restaurants, schools, daycare centers, office buildings me dical institutions, nursing homes, hospitals, and in the home. Surfaces treated with these products include; but are not limited to: floors, walls, sinks, countertops, textiles (laundering and soaking of diapers, baby clothing, adult clothing, etc), and other non por ous surfaces (e.g. children’s toys). One label includes the use of this pine oil-contai ning product in dog baths. This use will not be assessed as a part of registration review becau se it is expected to be removed from the label. In the event it is not removed from the label, then it will need to be assessed as a conventional use pesticide.

The Agency anticipates that new toxicologica l end-points will need to be selected and

new human health assessments will need to be conducted. The specific exposurePage 3 of 29 scenarios the Agency anticipates assessing is presented in Tables 4 through 6 and the anticipated data need are out lined in Section 10. New risk assessments for registration review will address the following exposures:

 Dietary (indirect food),

 Residential applicator,

 Residential post application,

 Aggregate,

 Occupational handler, and

 Occupational post application.

Section 1. Chemical Identity

Pine Oil is a blend of chemicals that t ogether, range in appearance from a colorless liquid to a pale yellow liquid. Pine Oil is a liq uid at 25oC that is insoluble in water, but soluble in organic solvents such as toluene and isopropyl alcohol. The density is 7.94 lb/gal (0.952 g/cm 3 ) at 20 o C and has a molecular weight of 154.0 g/mole. The vapor pressure is 1.27 torr at 25 o C and the boiling point is 208 o C (D248587).

Table 1. Chemical Identity and Properties

Common

Name Pine Oil

CAS name Pine Oil

PC Code 067002 CAS registry

number 8002-09-3

Registration

Review Case

No. 3113

Structure

Section 2. Toxicology

Acute Toxicity

In acute toxicity studies, pine oil has been shown to have low toxicity by the oral route (Toxicity Category III), dermal route (T oxicity Category III) and inhalation route (Toxicity Category IV). Pine oil is a moderate skin irrita nt (Toxicity Ca tegory III), but shows a stronger response as an eye irritant (Toxicity Category II). The available dermal sensitization assay conducted with pine o il is considered unacceptable because an inadequate number of animals were used to make a determination of sensitization and positive controls were not tested in this study. The pine oil RED, published in 2006, identified the dermal (skin) sensitization study (OPPTS 870.2600) as a data gap. Acute toxicity for pine oil is presented below in Table 2.Page 4 of 29 Table 2. Acute Toxicity Data for Pine Oil Technical Grade Active Ingredient (97.9-100%)

Guideline Number Study Type MRID

Number Results Toxicity Category

870.1100 Acute oral toxicity 40253502 LD 50 (males) = 3100 mg/kg

LD 50 (females) = 2100 mg/kg

LD 50 (combined) = 2700 mg/kg (M+F) III

870.1200 Acute dermal toxicity 40253503 LD 50 > 2000 mg/kg (M and F) III

870.1300 Acute inhalation toxicity 43375208 LC 50 > 3.67 mg/L IV

870.2400 Acute eye irritation 43375209 Moderate irritation (corneal opacity,iritis,conjuctival irritation up to 16 days postapplication) II

870.2500 Acute dermal irritation 43375210 Slight irritation (erythema up to 7 days, edema up to 4 days post-application) III

870.2600 Skin sensitization 43375211 Unacceptable Study NA

M = males; F = females; NA = not applicable

Subchronic Toxicity

The database for subchronic toxicity of pine oil consists of a 90-day dermal toxicity study in rats. Included in this study is a 14- day dose range-finding study that was used to establish doses for the main study.

In the 90-day dermal toxicity study (MRI D 40515401) conducted in the rat, pine oil (blend 1687) applied to the skin at dose s of 0, 50, 113 or 226 mg/kg/day produced no systemic, treatment-related effects on mo rtality, clinical signs, body weight, food consumption, hematology, clinical chemis try, organ weights or gross pathology. Although dermal irritation was observed in this study, the inciden ce and severity of erythemia, desquamation and scabbing was not observed consistently within groups of treated rats and did not appear to be dose -related. For microscopic dermal changes, acanthosis and hyperkeratosis observed in rats treated with 226 mg /kg/day pine oil had similar incidences when compared with contro l animals. An accurate determination of a NOAEL in this 90-day dermal study was furt her complicated by us e of a non-guideline dosing methodology and omission of some essentia l data, specific orga n weights, clinical chemistries and hematology parameters. Howe ver, when tested over a broader dose range (47, 235, 470, 940, 3,760 or 7,520 mg/kg/day) usi ng similar (non-guideline) testing methodologies for 14 days, dermal applicati on of pine oil resulted in dose-related

increases in incidence and seve rity of dermal irritation from 47 to 7,520 mg/kg/day as well as systemic decreases in mean body we ight, mean body weight gain and food consumption at 3,760 mg/kg/day. These dose-range finding data suggest that the systemic toxicity NOAEL is less than or equal to 940 mg /kg/day, a dose close to the test limit dose (1,000 mg/kg/day). Considering the systemic toxi city and dermal irritation results of the 90-day and 14-day dermal studies, a cons ervative systemic toxicity NOAEL of 226 mg/kg/day was approximated for the 90-da y dermal toxicity study (acceptable/nonguideline) and subsequently used in assessi ng risks from potential dermal exposures to pine oil.Page 5 of 29 Subchronic toxicity testing of pine oil via other routes of exposure remains inadequate. No studies are available which address poten tial subchronic toxici ty via the oral or

inhalation routes from the indi rect food and non-food uses of pine oil-containing pesticide products.

In the RED, the Agency held the requirem ent for a subchronic oral toxicity study (with additional neurotoxicity evalua tions) in reserve pending submi ssion of food residue data.

In the absence of additional data that addresse s the potential presence of pine oil in foods from the cleaning of countertops and othe r hard, non porous surfaces using currently registered products and the obser vation of neurotoxicity (ataxi a, decreased motor control, impaired righting reflex prior to death) in the existing pine oil toxicity data base, the Agency is anticipating that a 90-day subchr onic (oral) toxicity study (OPPTS 870.3100) as well as a 90-day (oral) neurotoxicity study (OPPTS 870.6200) will be needed to adequately characterize the hazard from pot ential oral exposures to pine oil (see Neurotoxicity).

For assessing potential inha lation exposures, a repeat-dose inhalation toxicity study is unavailable in the pine oil toxicity da ta base. Based on the use of pine oil disinfectant/cleaning pr oducts in occupational and re sidential settings via wiping, mopping, brushing, spraying, fogging, foaming and open pouring of these products or immersion into these products, the Agency is requiring a su bchronic inhalation toxicity study (OPPTS 870.3465). The data/information fr om a subchronic inhalation toxicity study is critical for the proper characterizati on and quantification of hazard and risk to human health from potential inhalation e xposures to pine oil.

Prenatal Developmental Toxicity

In a prenatal developmental toxicity study in rats (MRID 40515201), dams were administered pine oil via gavage at dose le vels of 0, 50, 600, or 1200 mg/kg/day from days 6-15 of gestation. Maternal toxicity in the form of excess salivation, alopecia, and ungroomed coat as well as decreases in food consumption, body weight and body weight gain were observed at doses of 600 and 1,200 mg/kg/day. Mortality occurring in animals administered 1,200 mg/kg/day pine oil exhibi ted ataxia, decreased motor activity, and impaired righting reflex prior to death, raisi ng the possibility of a neurotoxic effect. Further, increased adrenal gland weight was noted in dams administered 1,200 mg/kg/day. The maternal toxicity NOAEL established in this study is 50 mg/kg/day based on clinical observations, decreased body weight, body weight gain and food consumption observed at the LOAEL of 600 mg/kg/day. Dams trea ted with 600 and 1,200 mg/kg/day pine oil produced fetuses with decreased body weights in males only and both sexes, respectively. Fetal malformations, which included small eye orbit, microphthalmia, and depressed eye bulge, were reported in the 1,200 mg/kg/da y dosage group. Additionally, skeletal

examination showed increased fetal and litter inci dence of non-ossified or incompletely ossified skull, vertebrae, ma nubrium, sternebrae, and pelvis while visceral examination

showed dilation of the lateral ventricles (possible delayed brain growth) at 1,200 mg/kg/day. The developmental toxicity NOAEL es tablished for this study is 50 mg/kg/day based on decreased fetal weight, increased inci dences of fetal malformations and delayed

ossifications observed at the LOAEL of 600 mg/kg/day. This study is classifiedPage 6 of 29 acceptable-guideline for a prenatal developmen tal toxicity study in rats [OPPTS 870.3700; OECD 414] and is adequate for risk assessment purposes.

Reproduction and Fertil ity Effects Toxicity

Although the Agency’s earlier decision (reregi stration eligibility decision; RED, 2006) held the requirement of a two-generation repr oduction and fertility effects study for pine oil in reserve, reproductive toxic ity data is not part of the requ ired Tier 1 toxicity testing to support registration of pine oil pesticide products. Consequently, a reproduction and fertility effects study conducted with pine oil is not requir ed at this time.

Chronic Toxicity

Chronic toxicity data are not required at this time since there are no chronic exposures

based on the current labeled us e patterns for pine oil.

Carcinogenicity

Pine oil has not been classifi ed as to its carcinogenicity. However, carcinogenicity data are not part of the required Ti er 1 testing to support regist ration of pine oil pesticide products and therefore, are not required at this time.

Mutagenicity

Acceptable mutagenicity studies including a reverse gene mutation (Ames) assay, a mouse micronucleus assay and an unscheduled DNA synthesis assay were conducted with either pine oil blend 012494 or 1687. No mutagenic or genotoxic responses were

observed in these studies. In an in vitro mammalian cell gene mutation test, a negative mutagenic response was also observed for this chemical; however, this study was deemed unacceptable due to problems with the integr ity (contamination) of the cell cultures. According to the pine oil RED published in 2006, an i n vitro mammalian chromosome aberration test was identified as a data gap . The existing mutagenicity battery and description of test results for pine oil is presented below in Table 3.

Table 3. Mutagenicity Battery Studies for Pine Oil

Guideline, Study Type

MRID/Classification Description of Results

870.5100 (84-2) Reverse Bacterial Gene Mutation (Ames) Assay

MRID 43375212

Classification: Acceptable Pine Oil Blend 012494 showed no evidence of a mutagenic effect (no increase in induced mutant colonies over background) at concentrations of 0.1, 1.0, 100, 1000, or 10000 μg/plate using S. typhimurium strains TA 98, 100, 1535 and 1537 with or without

metabolic activation.Page 7 of 29 870.5300 (84-2) In vitro Mammalian Cell

Gene Mutation Test

MRID 40341402

Classification: Unacceptable Pine Oil Blend 1687 showed no ev idence of genotoxicity (increase of induction of mutant colonies over background) in Chinese Hamster Ovary (CHO) cells exposed at concentration of 100, 130, 170, 200 or 250 nl/ml (-S9 activation) and 50, 100, 200, 300 or 400 nl/ml (+S9 activation). This study is classified unacceptable because mycoplasm contamination was not monitored and several cultures were lost due to contamination during conduct of the

assay.

870.5395 (84-2) Mammalian Erythrocyte

Micronucleus Test

MRID 403414403

Classification: Acceptable Pine Oil Blend 1687 is not mutagenic since it did not cause a significant increase in micronucl eated polychromatic erythrocytes when administered via single i.p. injection to mice at doses of 116, 578 or 1155 mg/kg, in the presence or absence of metabolic

activation.

870. 5550 (84-2) Unscheduled DNA Synthesis in Rat Primary Hepatocytes with a Confirmatory Assay

MRID 40341404

Classification: Acceptable Pine Oil Blend CSMA 1687 did not indicate a positive mutagenic response (no significant increase in net nuclear grain counts of rat primary hepatocytes) at dose levels up to and including 0.03 μg/ml. Dose levels tested above 0.03 μg/ml were found to be cytotoxic.

Neurotoxicity

Based on the absence of oral subchronic toxi city data and the obs ervation of potential neurotoxic effects (ataxia, decr eased motor control, impaired ri ghting reflex prior to death) in the rat prenatal toxicity study, the Agency held a subchr onic oral toxicity study (with additional neurotoxicity eval uations) in reserve pending subm ission of food residue data (Pine Oil RED, 2005). However, no data have been submitted which address the potential presence of pine oil in foods that may occu r following use (indirect- food) of registered pesticide products containing pine oil. Cons equently, the data base for neurotoxicity remains incomplete. A 90-day oral neurotoxicity study is anticipated as needed to properly characterize potential ne urotoxic risks from repeat or al exposures to pine oilcontaining products (see Subchronic Toxicity).

Dermal Penetration

Dermal penetration data are not required at this time.

Metabolism and Pharmacokinetics

Metabolism and pharmacokinetic data are not required at this time.

Toxicity Endpoint Selection fo r Human Health Assessments

On February 24, 2004, the Antimicrobials Di vision’s Toxicity Endpoint Selection Committee (ADTC) reviewed the available toxi cology data for pine oil and considered toxicological doses and endpoints for use as appropriate in acute dietary (general population and females 13+ RfDs) and chronic dietary (RfD) exposure scenarios as well as toxicological doses, endpoints, data base un certainty factors, FQPA safety factors and a target margin of exposure (MOE) for non-dietar y, short-term/intermediate-term incidental oral (residential), short-term/intermediate-term dermal (occupational/residential) and short-term/intermediate-term inhalation (occupa tional/residential) expos ure scenarios. ForPage 8 of 29 a detailed summary, see Antimicrobials Di vision’s Toxicity Endpoint Selection Committee (ADTC) report for pine oil.

However, the existing doses, endpoints, data base uncertainty factors, FQPA safety factor and target MOEs are subject to reev aluation during registra tion review including any new toxicity data via future submissi ons/literature publications which may become available for pine oil.

Section 3. Dietary Assessment

Dietary Exposure

As provided in the RED (USEPA, 2006a ), the Antimicrobials Division (AD) considered potential dietary exposures to pi ne oil residues in food (see Table 4). Several registered product labels exist in which pine oi l is used as a disinfectant in restaurants, kitchens, cafeteria, food storag e areas, counter tops, stove to ps, drain boards, microwaves, food processing plants, and pi cnic tables. The Agency has relied on conservative assumptions and methodologies developed by the Food and Drug Administration (FDA) to estimate dietary exposures resulting from the indirect food contact uses of pine oil, however, to include the additional data required as a part of registration review, a dietary assessment will need to be completed.

Pine oil is exempt from the requirement of a tolerance under 40 CFR 180.1035 for use in honey and beeswax. Currently there are no registered products for this use; therefore, as recommended in the RED, the Agency is upholdi ng the recommendation that this tolerance is revoked as a part of registration review.

Drinking Water Exposure

All registered uses of pine oil are indoors and are not likely to contaminate surface or ground water. In the event that pine oil is released into a wa ste stream (chemically, pine oil consists mainly of cyclic trepan al cohols but also contai ns terpene hydrocarbons, ethers, and esters), its constituents are exp ected to volatilize rapidly from surface water, are highly biodegradable, have s hort half-lives in water, and have low mobility in soils. Hence, as concluded in the RED, there is low probability of surface or ground water contamination and a drinking water assessm ent is not needed (USEPA, 2006a).

Table 4: Dietary Use Patterns for Pine Oil

Scenario Use Patterns Route of Exposure

Dietary Exposure Cleaning of countertops and other hard non porous surfaces in eating areas *

Food Processing Facilities

Beverage Processing Facilities Ingestion of residues

*Utensils and glassware are restricted from being cleaned with pine oil products.Page 9 of 29 Section 4. Residential Handler and Post Application Exposure and Risk

Pine oil, found in many residential-use pr oducts, is used as a cleaner, disinfectant, sanitizer, fungicide, mildewstat, and deodorizer . The handler scenarios used in the past residential exposure assessment were selected to encompass multiple uses, and at the same time, represent high end exposures. The two us es assessed included the handling of liquid general purpose cleaners (via the methods of mopping and wiping) and dog wash use for the dermal (intermediate-term only) and i nhalation routes. The dog wash use will not be assessed as a part of registration review becau se it is expected to be removed from the label. In the event it is not removed from the label, then it will need to be assessed as a conventional use pesticide.

Short-term handler exposures via the dermal and inhalation (to both aerosol and vapor)

routes will need to be assessed for the scen arios that were considered in the RED along with additional use patterns that were not incl uded (identified in Table 5). As provided in the RED, there are also uncertainties associat ed with the surrogate databases that were utilized in completing the assessment. For all of the aforementi oned reasons, an updated residential handler exposure assessment will be require d for registration review.

Table 5: Summary of Use Patterns for Pine Oil

Scenario Use Patterns Route of Exposure

Residential Handler Residential homeowner cleaning with a product containing pine oil via:

Wiping Mopping Trigger Pump Spray

Liquid Open Pour Low Pressure Spray

Brush

Immersion Dermal

Inhalation (aerosol and vapor) b

Residential Post

Application Children crawling on cleaned floors

Children mouthing cleaned toys

Adult and Children Laundered Clothing

Adult and Children Pre-soaked Clothing a Dermal

Inhalation (vapor) b

Incidental Oral

a The use of pre-soaking baby clothes and diapers does not indicate laundering. If the label, Reg. # 82771-1 is revised to indicate laundering post-soaking, then an assessment of laundering with pine oil containing products will only be necessary.

b The vapor pressure is 0.2 mm Hg at 20°C (USEPA, 2006a), which is greater than the EPA cutoff of E-4 mmHg, therefore warranting an assessment of exposures to vapors.Page 10 of 29 The residential post-application scenario c onsidered for the RED includes exposure to residue from hard surfaces (i.e., floors) that have been mopped with a product containing pine oil along with th e laundering of clothing. The launderi ng of textiles and discussions of this use pattern are presented in an a ddendum to the RED (USEPA, 2006b). Pine oil has a relatively high vapor pressure (0.2 mmH g @ 20 C), such that there is concern for potential vapor inhala tion exposure.

Additional routes of post-a pplication exposures have b een identified upon review of the registered labels. There are also uncertainti es associated with the assumptions used in the post-application assessment in support of the RED (i.e. pe rcent transfer of residues from cleaned floor, leaching of pine oil from th e laundered textiles, etc) that will need to be addressed. Upon a submission of the necessary information, a post application exposure assessment will be completed for re gistration review, as appropriate, additional scenarios will be incorporated into the revised aggregate assessment.

Section 5. Aggregate Exposure and Risk

A short-term aggregate assessment was not conducted in the pine oils RED since a short-term toxicological endpoint was not sele cted. For the RED, the adult exposures from dietary exposures and inhalation exposures resulting from mopping we re aggregated, but omitted exposures resulting from wiping with hard surface cleaners. For exposures to toddlers, only the short-term incidental oral exposure resulting from cleaning floors with pine oil containing products (pos t application) were aggregated with dietary exposures. An intermediate term aggregate assessment will need to be considered as a part of registration review, as one was not completed for the RED.

Upon a reevaluation and selection of toxi cological endpoints, combined with the revised dietary and residential exposure assessmen t expected as a part of this registration review case, the aggregate assessment will need to be revised to include additional scenarios for the routes of dietary and reside ntial exposures along with both the short- and

intermediate-term durations. The values re presenting aggregate exposure and risks will need to be recalculated as a part of this registration review case.

Section 6. Occupational Handler and Post Application Exposure and Risk

Short-term inhalation exposures and in termediate-term dermal and inhalation exposures from contact with pine oil were assessed for handling pine oil-containing cleaning products via low pressure spray, wiping, and mopping applications (USEPA, 2006a). Post application exposures via the dermal and inhalation routes were deemed likely to be minimal when compared to handl er exposure because of product dilution with water. Therefore, for the RED, a separate screening-level assessment was not conducted for occupational post ap plication scenarios.

The occupational exposure assessment ut ilized surrogate databases, for which uncertainties have been identified. Also, upon a review of the registered labels, additional occupational scenarios were identified and will need to be assessed. Based on these conclusions, an occupational risk assessmen t will be required to support registration

review. It also needs to be considered that based on a review of data that are submitted inPage 11 of 29 response to the RED and registration review of pine oil, assessment of post-application occupational exposures may become necessary.

Table 6: Occupational Summary of Use Patterns for Pine Oil

Scenario Use Patterns Route of Exposure

Occupational Handler Occupational (i.e. janitorial) worker cleaning with a product containing pine oil via: Wiping Mopping Trigger Pump Spray

Liquid Open Pour Low Pressure Spray High Pressure Spray a Coarse Mechanical Spray

Brush

Immersion Foaming Apparatus Fogging (wet misting) Systems Dermal

Inhalation (aerosol and vapor) b

Bystander Exposure Bystanders in the vicinity of an area that is being cleaned Inhalation (vapor) b

a EPA Reg. #4313-14 includes this use pattern for occupational handlers, and is not carried out by residential handlers; hence this is why the use pattern is not necessary to assessed for residential handlers.

b The vapor pressure is 0.2 mm Hg at 20°C (USEPA, 2006a), which is greater than the EPA cutoff of E-4 mmHg, therefore warranting an assessment of exposures to vapors

Section 7. Incidents

There are 283 pine oil related human incide nts that have been reported to the EPA’s Office of Pesticide Program’s Incident Da tabase (IDS). Oral, de rmal, inhalation, and ocular exposures have all been reported.

Ingestion of pine oil products is freque ntly reported. In IDS, there have been 13 reported death incident cases as a result of i ngestion of pine oil c ontaining products (some ingestions may be due to pine oil’s pl easant aroma). The most common symptoms reported for oral exposure include: coughi ng, choking, vomiting, nausea, abdominal pain, shortness of breath, drowsiness, leth argy, and loss of consciousness.

The most common symptoms reported for cas es involving dermal exposure were skin irritation/burning, rash, itching, skin discoloration/redness. Symptoms associated with allergic skin reactions in clude blisters, and hives.

The most common symptoms reported for cases involving inhalation exposure were coughing, choking, sneezing, respiratory irrita tion/burning, asthma/difficult breathing,Page 12 of 29 shortness of breath, and respir atory depression. Reported in cidents for inhalation also include headaches, shaking, numbness, dr owsiness, lethargy and unconsciousness.

Ocular effects including eye irritation (burning and redness), corneal abrasion, eye swelling, eye discharge/infection and visual defect/blurred vision are common symptoms that have been reported with use of pine oil-containing products.

Section 8. Cumulative

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to Pine Oil and any other substanc es and Pine Oil does not appear to produce a toxic metabolite produced by other substances. For the purposes of this action, therefore,

EPA has not assumed that Pine Oil has a co mmon mechanism of toxicity with other substances. For information regarding EPA’s ef forts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’ s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from

substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

Section 9. Endocrine Disruption

As required by FIFRA and FFDCA, EPA revi ews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute,

subchronic and chronic toxici ty, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocri ne influence, including effects on endocrine target organ histopathology, or gan weights, estrus cyclicit y, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests a nd chronic studies that assess growth, developmental and reproductive effects in di fferent taxonomic groups. As part of the reregistration hazard assessment for Pine Oil

, EPA reviewed these data and selected the most sensitive endpoints for relevant risk as sessment scenarios from the existing hazard database. However, as required by FFDCA s ection 408(p), Pine Oil is subject to the endocrine screening part of the Endocrine Disruptor Screenin g Program (EDSP).

EPA has developed the EDSP to determin e whether certain substances (including pesticide active and other ingred ients) may have an effect in humans or wildlife similar to an effect produced by a “natur ally occurring estrogen, or othe r such endocrine effects as the Administrator may designate.” The ED SP employs a two-tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substan ce to interact with the estrogen, androgen, or thyroid (E, A, or T) hormona l systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adversePage 13 of 29 endocrine-related effects caused by the s ubstance, and estab lish a dose-response relationship between the dose a nd the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issu ed test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Pine Oil is not among the gr oup of 58 pesticide active ingredients on the

initial list to be screened unde r the EDSP. Accordingly, as part of registration EPA will

issue future EDSP orders/data cal l-ins, requiring the submissi on of EDSP screening assays

for Pine Oil. For further information on the stat us of the EDSP, the policies and procedures, the list of 67 chemicals, futu re lists, the test guide lines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/ .review,

Section 10. Conclusions

a. Data Needs

The Antimicrobial Division (AD) anti cipates requiring further exposure and toxicity studies will be required for registra tion review, as submission of these studies will permit an assessment of se veral residential and occ upational handler and post application/bystander scenarios. Table 7 lists the toxicity data needs and the rationales for these data requirements. Appendix A provides the toxicity data jus tifications. Appendix B provides the dietary data justifications. Tabl e 8 provides a summary of exposure scenarios and data needs. The exposure data jus tifications are provided in Appendix C.

Table 7. Toxicity Studies Needed for Pine Oil Registration Review Study Needed Guideline Rationale

90-Day Oral Toxicity 870.3100* Pine oil disinfectant and cleaning products applied to hard, non-porous surfaces in occupational and residential settings may result in dietary (indirect food) exposures in

children and adults and/or incidental oral (hand-to-mouth) exposures in children. The Agency is requiring a 90-day subchronic (oral) toxicity study because: (1) this study is a guideline required test under 40 CFR Part 158, (2) it is one of the Tier I mammalian toxicity data requirements for registration of indirectfood-use pesticides, (3) the lack of routespecific, repeat-dose (oral) toxicity data precludes estimation of the magnitude of potential dietary risks to humans from indirect-food uses of pine oil products for disinfection/sanitization purposes in occupational and residential settings, (4) ingestion of pine oil products is the most frequently reported route of poisoning in humans, and (5) data from a subchronic (oral) toxicity study conducted with pine oil would provide a more complete characterization ofPage 14 of 29 overall mammalian toxicity and a better understanding of the effects of pine oil on

human health.

90-Day Inhalation Toxicity 870.3465 Pine oil disinfectants and cleaning products are used in occupational and residential settings via wiping, mopping, brushing, spraying, fogging, foaming and liquid open pouring of these products or immersion into these products. A route-specific, subchronic toxicity study is critical for proper characterization and quantification of hazard and risk to human health from potential inhalation exposures to pine oil. Before initiating the study, registrants should consult

with EPA to determine if the inhalation toxicity study should be based on vapors or aerosols. Worker exposure is likely to occur to both vapors and aerosols.

90-Day Oral Neurotoxicity (Subchronic; Neurotoxicity Screening Battery) 870.6200* A 90-day subchronic (oral) neurotoxicity study for pine oil is required because (1) the existing chemical toxicity data base shows evidence of neurotoxicity as was noted in the acute oral, acute inhalation and the prenatal developmental toxicity studies, (2) other

chemicals within the same class as the active ingredient (i.e., terpenoids) are known neurotoxic agents, (3) there is the potential for dietary exposures to children and adults from the indirect-food uses (application of pine oil disinfectants and cleaning products to hard, non-porous surfaces) of pine oil-containing pesticide products in occupational and residential settings, and (4) data obtained from a 90-day (oral) neurotoxicity study may provide critical scientific information (neurotoxic effects) via the oral route of exposure as well as a dose and toxicological endpoint of concern for quantification of risksfrom the indirect-food uses of pine oilcontaining pesticide products.
*The Agency will accept a combined 90-day oral and 90-day neurotoxicity study. The combined study would follow the 90-day (oral) subchronic toxicity guideline and incorporate additional neurotoxicity evaluations in the testing paradigm. For a combined study, it is recommended that a protocol be submitted to the Agency for review prior to initiation of the study.Page 15 of 29 Table 8. Exposure Studies Needed for Pine Oil Registration Review

Study Needed Guideline Rationale

Indoor Exposure (several routes of exposures in the indoor setting) 875.1200

875.1400

875.1600

875.2500

875.2800 Exposures via the dermal and inhalation routes may occur during the handling and application of pine oil containing products via open pouring of concentrate, wiping, mopping, trigger pump spray, low pressure spray, brushing, and immersion.

Also based on the vapor pressure of this chemical there is concern for bystanders in the vicinity of a room that is being cleaned.

Surface Residue Dissipation (toys, textiles) 875.2300

875.2800

875.2900 Incidental oral exposures from hand to mouth activities may occur as a result of product application to surfaces (floors, toys)

Incidental oral and dermal exposures may occur from children wearing laundered or soaked items of clothing.

Nature of the Residue on

Surfaces

Migration Study No Guideline Child and adult dietary exposures as a result of

p ine oil containing products being used to clean hard non porous surfaces in food settings such as kitchen countertops.

Product Use information & Description of Human Activity 875.1700

875.2700

875.2800 Use information and human activity will be useful when evaluating exposures and assist in the planning of exposure studies.

a. Label issues

To reduce residential exposure, the Agency recommended in the RED that label mitigation language be added to limit the “full strength” rates (i.e., treatment solutions above 0.31%) to a maximum dilution rate of 0.31%. It has been noted that some of the recent labels have not been changed to reflect the mitigation stated in the RED.

Section 11. Reliance on Human Studies

Past pine oil risk assessments have not relied to any extent on human studies.

There is therefore no current need to a ddress the scientific soundness, ethicalPage 16 of 29 acceptability, need for review by the Human St udies Review Board, etc. that are often required to utilize certain research involving in tentional exposure of human subjects in an

EPA risk assessment.

Section 12. References

USEPA, 2011. PINE OIL (1-Methyl-4-isopropyl-1-cyclo-hexen-8-ol): Revised Toxicology Hazard Characterization for the Human Health Assessment Scoping Document in Support of Registration Review of Pine Oil. Memorandum from M. Centra. March 16, 2012

USEPA, 2011. PINE OIL (1-Methyl-4-isopropyl-1-cyclo-hexen-8-ol): Revised Toxicology Hazard Characterization for the Human Health Assessment Scoping Document in Support of Registration Revi ew of Pine Oil. TXR 1003232. Memorandum from M. Centra. D395481. January 25, 2012

USEPA, 2006a. Reregistration Eligibility Do cument for Pine Oil. Case 3113. September

2006.

USEPA, 2006b. Addendum to Residential Occupa tional and Residential Exposure Assessment of Pine Oil for the Reregistrati on Eligibility Decision Document (RED). Memorandum from C. Walls. June 26, 2006.

D395482. Memorandum from T. Li ndheimer, Chemist to N. Mottl, Biologist. Subject: Summary of Dietary, Reside ntial and Occupational Exposures for the Pine Oil Registration Review Scopi ng Document. January 20, 2012.

D248587. Memorandum from C. Jiang, Chemist to Julie Fairfax, Product Manager, Team 36. Subject: Review of Product Chemistry Package for the Pure Active Ingredients (PAI’s) for Pine Oil. October 1, 2007.Page 17 of 29 Appendix A. Toxicity Data JustificationsPage 18 of 29 Guideline Numb er: 870.3100* Study Title: 90-Day Oral Toxicity

Rationale for Requiring the Data

The Agency is requiring a 90-day subchronic (oral) toxicity study because: (1) this study is a required test guideline under 40 CFR Part 158, (2) it is one of the Tier I mammalian toxicity data requirements for registration of indirect food-use pesticides, (3) the lack of route-specific, rep eat-dose (oral) toxicity data precludes estimation of the magnitude of potential dietary risks to humans from indirect-food uses of pine oil products for disinfection/sanitization purposes in occupational and reside ntial settings, (4) ingestion of pine oil products is the most frequently reported route of poisoning in humans, and (5) data from a subchronic (oral) toxicity study conducted with pine oil would provide a more complete ch aracterization of overall mamm alian toxicity and a better understanding of the effects of pine oil on human health.

Practical Utility of the Data

1. How will the data be used?

The 90-day (oral) subchronic toxicity study is intended to provide critical scientific in formation (potential systemic toxicities) associated with repeated, ro ute-specific (oral) exposures to pesticide products containing pine oil for a period of 90 days. Data obtained from a subchronic toxicity study conducted via the oral route of exposure may also provide a dose and a toxicological endpoint of concern for quantification of risks from the indirect food-uses of pine oil in occupational and residential settings.

2. How could the data impact th e Agency’s future decision-making?

The Agency could establish a dose and to xicological endpoint from this study that is more conservative than the doses/endpoints currently used to conduct quantitative risk asse ssments for pine oil. If used as the source of a dose and toxicological endpoint for route-specifi c (oral) risk calculations, these new data would provide an estimate of the magnitude of this potential risk as well as providing a mo re complete characterization of overall mammalian toxicity and a better understanding of the effects of pine oil on human health.

*The Agency will accept a combined 90-day oral and 90-day neurotoxicity study. The combined study would follow the 90-day (oral) subchronic toxicity guideline and incorporate additional neurotoxicity evaluations in the testing paradigm. For a combined study, it is recommended that a protocol be submitted to the Agency for review prior to initiation of the study.Page 19 of 29 Guideline Number/Study Title: 870.3465 90-Day Inhalation Toxicity

Rationale for Requiring the Data

Although the inhalation route is one of the major routes of potential human exposure to pine oil for several occupational and residential handler scenarios, a repeat-dose inhalation toxicity study is not available in the pine oil toxicology data base. Based on the use of pine oil disinfectants and cleaning products in occupational and residential settings via wiping, mopping, brushing, spraying, fogging, foaming and liquid open pouring of these products or immersion into these products, a route- specific subchronic toxicity study is critical for proper characterization and quantification of hazard and risk to human health from inha lation exposures to pine oil. Therefore, the Agency is requiring a repeat-dose (subchronic) inhalation toxicity study conducted with the active ingredient, pine oil.

Practical Utility of the Data

1. How will the data be used?

These data will allow the Agency to conclude more defin itively whether or not there are any concerns for potential inhalation toxicity from the indirect food-uses and non-food uses of pine oil-containing pesticide products. This study may also provide a dose and toxicological endpoint applicable to a quantitative inhalation risk assessment. A repeat-dose inhalation toxicity study can be designed to simulate both a real world route of human exposure as well as a specific duration of exposures to varying (vapor and ae rosol) concentrations of the test material. A detailed toxicological examination including the histopathology of the respiratory system would also be conducted in an inhalation toxicity study and thereby, provide a better understanding of potential adverse effects resulting from exposure to pine oil via the inhalation route.

2. How could the data impact th e Agency’s future decision-making?

In the absence of repeat inhalation toxicity data, the Agency is currently unable to estimate inhalation risks to persons using products which contain pine oil for disinfection/san itization purposes in occupational and residential settings. If used as the source of dose and effect for route-speci fic and duration appropriate inhalation risk calculations, information from a repeat-dose inhalation toxicity study would provide an estimate of the magnitude of this potential risk as well as providing a more complete characterizatio n of overall mammalian toxicity and a better understanding of the effects of pine oil on human health.Page 20 of 29 Guideline Numb er: 870.6200* Study Title: 90-Day Oral Ne urotoxicity (Subchronic; Neur otoxicity Screening Battery)

Rationale for Requiring the Data

The Neurotoxicity Screening Battery (OPPTS 870.6200) is desi gned to evaluate the poten tial adverse effects on the nervous system from exposure to pesticide chemicals. The Agency believes that existing pine oil studies are inadequate in their assessment of behavioral effects and do not use optimal methods to evaluate the potential toxicity

to the nervous tissue structure and func tion. To detect and characterize thes e potential effects more fully, more sensitive testing is required. The objective of this neurotoxicity testing is to eval uate the incidence and severity of the functional and/or behavioral effects, the level of motor activity, and the histopathology of the nervous system. The subchronic neurotoxicity study is intended to detect possible effects re sulting from repeated or long-term exposures. Therefore, the Agency is requiring a 90-day subchronic (oral) neurotoxicity study for pine oil. A neurotoxicity evaluation for pine oil must be conducted because (1) the existing chemical toxicity data base shows evidence of neurotoxicity as was noted in the acute oral, acute inhalatio n and the prenatal developmental toxicity studies and, (2) other chemicals within the same class as the active ingredient (i.e., terpenoids) are known neurotoxic agents and (3) there is the potential for dietary exposures from the indirect-food uses of pine oil-containing pesticide products in occupational and residential settings.

Practical Utility of the Data

1. How will the data be used?

A subchronic neurotoxicity study would provide critical scientific information needed to characterize potential hazard to mammalian nervous systems from exposure to pestic ides. For pine oil, this study can provide data on a wide range of functional tests for evaluating neurotoxicity including sensory effects, neuromuscular effects, learning and memory and histopathology of the nervous system. In addition, a neurotoxicity study can be used to select endpoints and doses for use in risk assessment of many ex posure scenarios and are considered a primary data source for reliable reference dose calculation. Furthermore, the Agency has established an oral reference dose (RfD) for assessing dietary risks for a number of chemicals where neurotoxicity was the most sensitive endpoint of concern (i.e., cholinesterase inhibition).

2. How could the data impact th e Agency’s future decision-making?

The Agency could establish a dose and toxicological endpoint from the new study that is more conservative than the doses/endpoints used previously (Pine Oil RED, 2006) to co nduct quantitative risk assessments for pine oil. If used as the source of a dose and toxicological endpoint for ro ute-specific (oral) risk calcu lations, these new data would provide an estimate of the magnitude of this potential risk, a more complete characterization of overall mammalian toxicity and a better understanding of the effects of pine oil on human health. In the absence of this data, additional database uncertainty factor may also be applied when conducting a risk assessment using the currently available studies, thereby increasing the Agency’s level of concern.

*The Agency will accept a combined 90-day oral and 90-day neurotoxicity study. The combined study would follow the 90-day (oral) subchronic toxicity guideline and incorporate additional neurotoxicity evaluations in the testing paradigm. For a combined study, it is recommended that a protocol be submitted to the Agency for review prior to initiation of the study.Page 21 of 29 Appendix B: Dietary Data JustificationsPage 22 of 29 Guideline Number: No Guideline Study Title: Nature of Residue on Surfaces Guideline Number: No Guideline Study Title: Migration Study Rationale for Requiring the Data

These residue chemistry studies will allow the Agency to conduct chemical-specific, quantitative dietary risk assessments that utilize the measured quantities of pine oil that will be available for dietary consumption when food contact surfaces that have been freshly treated with pine oil-containing products. The Nature of the Residue on Surfaces study will determine whether resi dues persist on treated food-contact su rfaces, the identity of those residues, and a measured upper limit on total surface residue level. The Migration Studies are au tomatically required but may be waived depending on the outcome of the Nature of th e Residue on Surfaces study. Migration Studies determine the concentrations of specific residues of toxicological concern transferred from treated food-contact surfaces to various types of food coming in contact with these surfaces. Data from these studies will replace any default leaching and migration rates used in earlier risk assessments.

The Agency initially assessed exposures to residues on counte r tops by assuming that 10% of the available pesticide migrates to the food commodity and is available for in gestion; this value is co mpletely arbitrary and may underestimate or overestimate exposure and human risk. Furthermore, no consideration was given to dissipation/loss of surface residues via volatilization, identity of degradates, or preferential migration of residues to certain types of food depending on porosity, water or fat content, etc.

Practical Utility of the Data

1. How will the data be used?

The Nature of the Residue on Surfaces study will be used to determine wh ether the active ingredient remains on the treated food-contact surface, whether it degrades, to what it degrades, and the upper limit on total food-contact surface residues. This study may negate the need for a dietar y risk assessment, may be used as an upper (yet more refined) exposure limit, and may be used to either waiv e or provide direction for the Migration Studies. MigrationStudies determine the concentrations of specific residues of toxicological concern transferred from treated foodcontact surfaces to various types of food coming in contact with these surfaces.

2. How could the data impact th e Agency’s future decision-making?

If pine oil residues transfer from treated surfaces to f ood, human exposure will occur. These studies will permit the conduct of chemical-specific, quantitative dietary risk assessments that are much more refined than earlier assessments and in which the Agency has higher confidence. This information will permit a determination of which use patterns are expected to result in exposures less than the Agency’s level of concern, which ones must be supported by additional data, and which ones are likely to have risks of concern and, therefore, must be mitigated. In addition, these data will permit a more realistic estimate of human aggregate risk.Page 23 of 29 Appendix C: Exposure Data JustificationsPage 24 of 29 Guideline Number: 875.1200 Study Title: Indoor Dermal Exposure
Rationale for Requiring the Data
Very limited worker exposure monitoring data are available for antimicrobial pesticides when considering the dermal route of exposure that results from handling pine oil contai ning products. Additionally there is limited data regarding the dermal exposures that may occur when individuals contact surfaces that are cleaned with such products. EPA used these limited data to perform screening level risk assessments for the pine oil RED.

The existing data in the Chemical Manufacturers Associ ation (CMA) database and Pesticide Handlers Exposure Database (PHED) for worker exposure scenarios are limit ed in scope and quality. The CMA data also has QA/QC problems, including the lack of field fortification, labora tory recoveries, and/or storage stability information. In

addition the CMA data have an insu fficient number of replicates.

EPA presented the need for additional handler exposure data to the January 2007 Science Advisory Panel (SAP) as well as to the April 2007 Human Studies Review Board (H SRB) and both groups agreed that additional data are

warranted.

To protect handlers from dermal exposures to pesticides, EPA requires dermal exposure monitoring data. The RED identified the lack of chemical-specific dermal exposure data , which this study will provide. The data are needed to support handler exposures for the residential and occupational users.

Practical Utility of the Data

1. How will the data be used?

The dermal exposure data will be used to assess the residential and occupational exposure to individuals cleaning and disinfecting a variety of hard non porous surfaces. The cl eaning processes are performed via a range of methods, and the generation of the dermal exposure data will allow method specific assessments to be completed.

2. How could the data impact th e Agency’s future decision-making?

The dermal exposure data will provide more accurate estima tions of the dermal risks to individuals using pine oil containing produc ts. These data will be used to generate a s ound risk assessment to mo re accurately reflect the actual exposure. If future risk assessments are performe d in the absence of these data, the Agency will have a significant degree of uncertainty in its regulatory decision-making process and current mitigation measures (i.e., personal protective equipment) may not provide adequate protection for workers that may contact pine oil in industrial settings. The lack of these data will limit the flexibility of the Agency and registrants with respect to decisions made from high-end screening level assessments that may overestimate exposures.Page 25 of 29 Guideline Number: 875.1400 Study Title: Indoor Inhalation Exposure

Guideline Number: 875.2500 Study Title: Inhalation Exposure (Post Application)

Rationale for Requiring the Data Note: Inhalation exposure data are needed for both residential and occupational uses.

For human risk assessments, exposures via the inhalation route from the use of a variety cleaning methods such as low pressure spraying or fogging, where aerosols would be generated are important to consider. In addition, inhalation exposures from liquid pouring are evident in expo sure studies in the Pesticide Handlers Exposure Database (PHED). The existing Chemical Manuf acturer Association (CMA) data base and PHED for these scenarios are limited in scope for QA/QC and number of monitoring units. EPA presented the need for additional handler exposure data to the January 2007 Science Advisory Panel (SAP) as well as to the April 2007 Human Studies Review Board (HSRB) and both groups agreed that additional data are warranted.

Specifically for pine oils, the Agency conducted a handler risk assessment using limited, preliminary exposure data as well as EFAST to calculate bystander inhalation exposu res to the post cleaning vapors that are expected to be generated (e.g. to children crawling on floors after cleaning . These use patterns triggers the need for chemical- and use pattern-specific residential and occupational exposure data upon which to base a robust quantitative risk

assessment.

This data requirement may be satisfied either by conducting an inhalation exposure monitoring study or by cooperating with the Ag ency to develop and conduct small chamber st udies to determine air emission rates, which then may be used to estimate inhalation exposure in occupational and residential settings. Practical Utility of the Data

1. How will the data be used?

The inhalation exposure data would be used to assess the residential short-term duration of cleaning with pine oilproducts. For occupational uses, the inhalation exposure data would be used to assess the short- and intermediateterm exposures from cleaning. These data will also be used to assess bystander exposures to the vapors that may result from the relatively high vapor pressure of pine oil.

2. How could the data impact th e Agency’s future decision-making?

The inhalation exposure data would be used to determine the accuracy of the inhalation risks to both residential and occupational workers using the formulated products in residential and industrial settings. If future risk assessments are performed without these data, the Agen cy will have to assume a significant degree of uncertainty in its regulatory decision-making process and current mitigation measures (i.e., personal protective equipment) may not provide adequate protection for workers that may contact pine oil in industrial settings. The lack of these data will limit the flexibility of the Agency and registrants with respect to decisions made from high-end screening level assessments that may overestimate exposures.Page 26 of 29 Guideline Number: 875.1600 and 875.2900 Study Title: Data Reporting and Calcul ations (Handler and Post Application) Rationale for Requiring the Data

This data requirement is linked to the dermal and inhalation exposure data also being required. The submission of these monitoring data serves as quality assurance and control (QA/QC) for the dermal and inhalation data. These data are intended to ensure that the product manufacturer and registrant conducting the study adhere to a defined set of quality criteria and meet the study requirements of the Ag ency. These data allow the Agency to determine if the quality of data provided will serve the risk assessment needs and support the registrant’s goal for product registration review. Submission of exposure monitoring data reporting increases the Agency’s confidence in the data submitted. Rationale for Requiring the Data/Practical Utility

1. How will the data be used?

These studies will be used to validate the data provided from the indoor dermal and inhalation applicator exposure studies. These data are important because it allows EPA to assess the adequacy and quality of the exposure study.

Information that must be submitted incl udes a description of the purpose of the study and what requirement(s) it is intended to satisfy, a summary of the study, a comprehensive section on materials, methods, and calculations, a section interpreting the scientific results of the study, a disc ussion of quality assurance, identification of the location of the raw data, and any references, communications, and protocols relevant to the conduct of the study.

2. How could the data impact th e Agency’s future decision-making?

The data will be needed to interpret the exposure data that ar e reported in support of this registration review process. If the exposure monitoring data reporting is not submitted in conjunction with the indoor dermal and inhalation applicator exposure studies, the Agency may not be able to utilize the studies to the fullest extent to conduct its human health exposure and risk assessments.Page 27 of 29 Guideline Number: 875.1700 and 875.2700 Study Title: Product Use Info rmation (Outdoor and Indoor)

Rationale for Requiring the Data

Product use information is a narrative description of which, when, and how materials are preserved when the product is actually applied; it is not a field study. A description of how products containing pine oils are used will provide a comprehensive, realistic assessment of its potential app lications and resulting handler and postharvest exposure. Descriptions are needed of: (i) what specific types of mate rials are treated; (ii) the cond itions to which pine oils will be exposed (temperatures, pH’s, etc); etc. These will pr ovide a comprehensive, realistic assessment of potential residential and occupational exposures. Therefore, these data are required.

Product use information permits EPA to more accurately assess pesticide exposure to applicators by describing how the pesticide is actually used and applie d. EPA requires this information becau se differences in use can translate to significant differences in exposure, and thus in risk. The Agency historically has used its best professional judgment based on its years of experience and general use information from the registered product labels, and product chemistry data.

The guideline for post application product use information was pres ented to the FIFRA Science Advisory Panel (SAP) in March 1998. (The draft guideline is available at http://www.epa.gov/scipoly/sap/meetings/1998/march/contents.htm .). The guideline for applicator product use information should be substantially similar to the one for postapplication. Practical Utility of the Data

1. How will the data be used?

The description of the materials preserved, application techniques, and degradation conditions will be used to determine the exposure scenarios for which exposure studies will be required for use in risk assessment. The description of the materials preserved, application te chniques, and physicochemical disposition will be used to determine the exposure scenarios for which exposure studies will be required for use in risk assessment and for the Agency to determine how representative the exposu re data are of the “real-world” use scenarios.

2. How could the data impact th e Agency’s future decision-making?

These data will enable the Agency to understand how the regi stered products are applied an d to ensure that the risk assessment is inclusive of the types of exposures occurring during pesticide use and from any potential post application contact. This information will permit a determination of which use patterns are expected to result in exposures less than the Agency’s level of concern, which ones must be supported by additional data, and which ones are likely to have risks of concern an d, therefore, must be mitigated.Page 28 of 29 Guideline Number: 875.2300 Study Title: Indoor Residue Dissipation

Rationale for Requiring the Data These leaching/migration data will allow the Agency to conduct chemical specific quantitative assessments that utilize the measured quantities of pine oil leaching/migrating from:

a) floors that have been freshly cleaned with a pine oil containing product b) clothing that has been laundered or pre soaked with pine oil containing products c) toys that have been cleaned with pine oil containing products d) food contact surfaces that have been freshl y cleaned with pine oil containing products

Data from these studies will replace any default leaching an d migration rates used in the risk assessment. The Agency specifically utilized the following generic non chemical-specific assumptions:

a) Regarding the quantity of solution residue left on the floor after cleaning, as a conservative measure, it has been assumed that 25% of the product remains after the final mopping. b) To quantify the percent transfer of pine oil from the fl oor, based on the Residential SOPs, it was assumed that 10% of the amount of product on the hard su rface is available for dermal transfer. c) For textiles (laundering), the chemical specific quantity of transfer of residues from cl othing to skin to confirm dermal exposures was identified as a data gap. d) Toys being cleaned with pine oil containing products have not been assessed previously and will be assessed as part of registration review. e) It was assumed that 10% of the available pesticide migrat es to the food commodity and is available for ingestion; this value will need to be supported or revised.

Practical Utility of the Data

1. How will the data be used?

The data would be used to determine the leachability and/or migration of the active ingredient as a percentage of the original retention.

2. How could the data impact th e Agency’s future decision-making?

If levels of pine oil transfer from cl eaned surfaces (floors and coun tertops) or soaked materi als (textiles), it may result in human exposure and risk. Chemical specific assessments have not been co mpleted due to the absence of data. This information will permit a determination of which use patterns are expected to result in exposures less than the Agency’s level of concern, which ones must be supported by additional data, and which ones are likely to have risks of concern and, therefore, must be mitigated.Page 29 of 29 Guideline Number: 875.2800 Study Title: Descriptions of Human Activi ty
Rationale for Requiring the Data Very limited worker activity data are available for antimic robial pesticides. Worker application parameters are generally defined by the physical nature of the formulation (e.g., formula and packaging), by the equipment required

to deliver the chemical to the use site , and by the application rate required to achieve an efficacious dose. The risk assessment noted that many of the use parameters used (e .g., amount handled and duration of use) were based on professional judgments judgment and general use information from the registered product labels, and product chemistry data, as well as from communication with the regist rants of registered products. These data are needed to fill this data gap and provide information needed to refine the risk assessment. Practical Utility of the Data

1. How will the data be used?

The discussion of human activity would be used to define the exposure scenarios to be assessed in the risk assessment. Additionally, a complete description of activit y patterns would ensure that the risk assessment is inclusive of the types of exposures occurring during residential and occupational use.

2. How could the data impact th e Agency’s future decision-making?

This information will allow the Agency to assess, with grea ter confidence, the risks that may result from contact with or use of antimicrobial products containing pine oil. This information will also permit appropriate label warnings, PPE, and any necessary risk mitigation.