Page 2 of 12 E XECUTIVE S UMMARY

EPA’s Health Effects Division (HED) has evaluated the available data and the most recent human health risk assessments for the repellent furanone to determine the scope of work necessary to support the registration review process. Furanone is the common name used to describe two active ingredients: dihydro

- 5

- pentyl

- 2(3H)

- furanone and dihydro

- 5

- heptyl

- 2(3H)

- furanone , also called tanol derivatives

. HED has considered the current use patterns (OPPIN Database and current labels) as well as the available toxicity and exposure information for f uranone

. The most recent human health risk assessment for furanone was conducted in for the Reregistration Elig ibility Decision ( J. Redden, 09/ 2 9 / 1995 ).

The purpose of the scoping process is to present the results of HED’s determin ation regarding the sufficien cy of available data to assess the safety of this pesticide, including any new data submitted since the last assessment that would necessitate conducting a new human health risk assessment to support registration review.

The two f uranone s addressed in this document are natural occurring compounds found in apricots and peaches. In addition, dihydro

- 5

- heptyl

- 2(3H)

- furanone is found in milk and meat products, and passion fruit. These are used as fragrance s and are registered by the FDA as food additives. However, they are not listed as “Generally Recognized as Safe” by the FDA. The toxicolog y database for the furanones does not contain all of the guideline studies required for a

non

- food use ; however, the furanones are natural products and approved for uses in foods and cosmetics at levels higher than currently allowed in registered pesticide products.

All the end

- use products containing furanones are co

- formulated with limonene but the latter is addressed separately (G. F. Kramer, D374492, 08/13/2011)

. Products containing furanones are not registered for food uses at this time. Currently, four products containing furanones are registered for non

- food uses ; in two these are included as active ingredients ( EPA Reg. No. 45987

- 1 and 66617

- 1) and in two as inert ingredients.

Since these compounds are widely used as flavoring agents and fragr ances, are naturally occurring, are present in registered pesticide prod ucts at very low levels result ing in very low exposures from pesticidal uses, and show minimal toxicity in available toxicity studies, additional toxicity and exp osure data are not req uired. Therefore, a quantitative risk assessment for pesticide

- related uses is not required.

1.0 F URANONE F ORMULATIONS AND U SE P ATTERNS

HED used the Biological and Economics Analysis Division (BEAD) Label Data System to identify all agricultural and non

- agricultural uses of furanone

. See Furanone HED Master Label Report ( 11/Mar/2011 ) for a complete list. The concentr ation s of the active ingredients in the end

- use products are: 0.024% for dihydro

- 5

- pentyl

- 2(3H)

- furanone and 0.049% for dihydro

- 5

- heptyl

- 2(3H)

- furanone

. Formulations containing the furanones as the active ingredient include (1) a granular dog and cat repellent and (2) an insect repellent wrist and ankle band . In addition,Page 3 of 12 two formulations including the furanones as inert ingredients were identified by the Pesticide Reregist ration Division. These a re discussed in the Confidential Appendix.

Agricultural Uses

End

- use products containing furanones are not registered for agricultural uses at this time.

Non

- Agricultural and Residential Uses

Pesticide products for residential uses containing furanones as active ingredients and inerts are listed in Appendix B.

2.0 H AZARD I DENTIFICATION /T OXICOLOGY

Although not being an FDA GRAS chemical, the furanones are ap proved as food additive s at levels up to 0.2% since they are naturally occurring compounds and exposures to low concentrations are considered safe at comparable concentrations of furanones used in cosmetic products (lotions, detergents, perfumes). Furanone pesticide prod ucts have maximum concentrations of 0.05%.

The acute toxicity results are classified as low

- toxicity ( C ategory IV) for the furanone formulations. However, the acute toxicity studies for the furanones were conducted on products also containing limonene.

Table 1. Acute toxicity studies for an animal repellent end

- use product 1 containing the furanones 2 and limonene.

Test R esults C ategory

Oral LD50

-- rat LD50 > 5 gm/kg IV

Dermal LD50

-- rabbi t LD50 of dry formulation > 5 gm/kg IV

Inhalation LC50

-- rat LC50 > 5 mg/l, using particle size of 297 microns or less. IV

Eye irritation

-- rabbit PIS

- Washed = 0.0. PIS

- Unwashed = 0.0 IV

Dermal irritation

-- rabbit PIS = 0.0 IV

De rmal sensitization

-- Guinea pig No sensitization using draize technique

----

1 From a mono gram of animal repellent # 100 (J. Redden, 09/29/1995).

2 Percent of the furanones in the end

- use product: 0.024% for dihydro

- 5

- pentyl

- 2(3H)

- furanone and 0.049% for dihydro

- 5

- heptyl

- 2(3H)

- furanone

. The following acute studies were performed with the active ingredient but are based in reports from the open literature:Page 4 of 12 - For dihydro

- 5

- pentyl

- 2(3H)

- furanone , the acute oral LD 50 in rats and guinea pigs was reported as 9780 (category III) and 3440 (category IV) mg/kg, respec tively (Jenner, Hagan, Taylor, Cook & Fitzhugh, 1964). The acute oral LD 50 in rats was reported as 6600 mg/kg (category IV, 5800

- 7400 mg/kg, Moreno, 1972a). The acute dermal LD 50 in rabbits exceeded 5000 mg/kg (category IV, Moreno, 1972b). D ihydro

- 5

- pent yl

- 2(3H)

- furanone applied full strength to intact or abraded rabbit skin for 24 hr under occlusion was slightly irritating (Moreno 1973b).

- For dihydro

- 5

- heptyl

- 2(3H)

- furanone , the acute oral LD 50 in rats was reported as 18500 mg/kg (category IV, Jenner, Hagan, Taylor, Cook & Fitzhugh. 1964). Fatty infiltration of liver parenchymal cells occurred in rats fed 13

- 115 mg dihydro

- 5

- heptyl

- 2(3H)

- furanone for 5

- 9 days (Shillinger, 1950).

In sub

- chronic studies, administration of dihydro

- 5

- heptyl

- 2(3H)

- furanone and dihydro

- 5

- pentyl

2(3H)

- furanone to rats for 90 days at levels in excess of at least 100 times the maximum estimated daily dietary intake in man evoked no adverse effect on growth, food consump tion, haematology, blood chemistry, liver and kidney weights or on gross and microscopic appearance of major organs at autopsy. When fifteen FDRL rats were fed at 14.6 and 62.8 mg/kg/day for 90 days, no significant gross pathological change was observed at autopsy in any rats. Several of the animals in the groups receiving the lactones showed various degrees of mild thyroid hyperplasia but this observation was also noted in the corresponding control groups and is not an uncommon finding in these laboratorie s (Food Cosmet. Toxicol. Vol. 3, pp. 563

- 569. Pergamon Press 1965).

In chronic studies, dihydro

- 5

- pentyl

- 2(3H)

- furanone at 0.1

- 0.5% fed to groups of 20 male and female rats in the diet for 2 years produced no effects. For dihydro

- 5

- heptyl

- 2(3H)

- furanone

, groups of 20 male and 20 female rats were fed diets containing 0.1 or 0.5% dihydro

- 5

- heptyl

2(3H)

- furanone for 2 years without any specific adverse effects. Both furanones in feeding studies at 0.1

- 0.5% for two years were reported to produce no effects wit h respect to carcinogenicity (Bar & Griepentrog, 1967; Food Cosmet. Toxicol. Vol. 12, pp 889 and 921, 1975).

Conclusion

The toxicology database for the furanones does not contain standard Part 158 guideline studies; the bulk of the toxicology investigations on the furanones are through the open literature. H owever, the furanones are natural product s and approved for uses in foods and cosmetics at levels higher than currently registered pesticide products. Based on the summary listed in the 1995 RED that the hazard of the furanones is limited, HED concludes that additional toxicity data are not required, and that a quantitative risk assessment for pesticide

- related uses is not required.

3.0 R ESIDUE C HEMISTRY

The furanone s are not currently registered as a pesticide for uses in food commodities ; therefore, evaluation of residues in crops is not needed

.Page 5 of 12 4.0 D IETARY E XPOSURE

The furanones are not currently registered for food

- uses in agricultural c ommodities. T urf us es of t he cat & dog repellent granule formulation may be assessed for residues in drinking water. However, the furanones are not soluble in water, are naturally occurring, are widely used as food additives and fragrances, are present in registered pestici de products at very low levels resulting in significant exposures f rom pesticide uses, and show minimal toxicit y in available toxicity studies. Based on this a dietary exposure assessment is not required for registration review

.

5.0 T OLERANCE A SSESSMENT A ND I NTERNATIONAL H ARMONIZATION

Tolerances are not established for furanone s since no registered pesticide uses in food commodities exist at this time.

6.0 R ESIDENTIAL E XPOSURE

Residential Handler and Post

- application Exposure

The products containing furanones as the active ingredient include cat and dog repellent granules, and impregnated material s (wrist and ankle band s )

. Moreover, two products containing the furanone as inerts are registered at this time . Residential exposure was not previously
qu antitatively assessed for either active or inert uses of the furanones. Since these compounds

are widely used as food additives and fragrances, are naturally occurring, are present in registered pesticide products at very low levels and likely to result i n very low exposures from pesticidal uses, as well as showing minimal toxicity in available toxicity studies, a quantitative residential handlers and postapplication exposure assessment is not required.

7.0 A GGREGATE E XPOSURE AND R ISK A SSESSMENT

In accordance with FQPA, HED considers and aggregates pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from dietary and residential sources are added together a nd compared to quantitative estimates of hazard (e.g., a NOAEL), or the risks themselves can be aggregated. Since quantitative risk assessments are not required for the furanones, an aggregate assessment is not needed for registration review.

8.0 O CCUPATIO NAL E XPOSURE

There is potential for occupational handler and postapplication exposure to furanone. However, a quantitative assessment for these uses in pesticide products was not previously performed and is still not required for the same rationale stated for the residential exposure section

.Page 6 of 12 9.0 P UBLIC H EALTH AND P ESTICIDE E PIDEMIOLOGY D ATA

K. Swe Oo, D 393554

, 09 / 0 7 /2011

T he OPP Incident Data System (IDS) w as utilized for pesticide incident data on the active ingredient furanone (PC Code 122301, 122302 ). The purpose of the database search is to identify potential patterns on the frequency and severity of the health effects attributed to furanones exposure. The IDS in cludes reports of alleged human health incidents from various sources, including mandatory Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6 (a) (2) reports from registrants, other federal and state health and environmental agencies and individual consumers. Since 1992, OPP compiles these reports in IDS. The IDS contain s reports from across the U.S. and most incidents have all relevant product information recorded. Reports submitted to the IDS represent anecdotal reports or allegations o nly, unless otherwise stated in the report.

IDS records incidents resulting in high er severity outcomes in more detail in a module called the Main IDS module . This system stores incident data for death, major and moderate incidents, and it includes mor e details about the location, date and nature of the incident. Main IDS incidents involving only one pesticide are considered to provide more certain information about the potential effects of exposure from the pesticide. The less severe human incidents (minor, unknown, or no effects outcomes) are reported by registrants as counts called aggregate summaries and are recorded in a separate module called Aggregate IDS

.

In A ggregate IDS , from January 1, 200 6 to April 26, 2011

, there are 116 incidents invo lving pesticide products containing the furanones. Because it falls within the categories reported as counts (which includes minor, unknown or no effects)

, there is no unique report that provides details about the incident and single chemical incidents ar e not distinguished from multiple chemical incidents; however, a high frequency of incidents indicates there is a high potential for exposure and vice versa. For f uranones, there appears to be some potential for exposure.

For the Main IDS, from January 1, 2006 to April 26, 2011, there are 10 cases reported that involve pesticide products containing the fura n ones as one of the active ingredients in the product. There are 5 cases in 2006, 3 cases in 2007 and one case each in 2008 and 2010. However, there is no case reported for single chemical furanone only in the database , since all furanone products are co

- formulated with other ingredients

. Another system used by HED to search for human incidents with pesticides is the A gricultural Health Study (AHS). The AHS is a high quality

, prospective epidemiology study evaluating the link between pesticide use and various health outcomes including cancer. Furanones are not included in the AHS.

Conclusions

Based on the low frequency and severity of incident cases, there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be i ncluded in the risk
assessment.Page 7 of 12 10.0 E NVIRONMENTAL J USTICE

Potential areas of environmental justice concerns, to the extent possible, will be considered in future human health risk assessments for furanone , in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

Income Populations," http://www.epa.go v/compliance/resources/policies/ej/exec_order_12898.pdf . The Office of Pesticide Programs (OPP) typically considers the highest potential exposures from the legal 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 diets within the U.S., and people who may be exposed when harvesting crops. Should these highest exposures indicate potential risks of concern, OPP further refine s the risk assessments to ensure that the risk estimates are based on the best available information.

11.0 C UMULATIVE R ISK A SSESSMENT

EPA does not have, at this time, available data to determine whether furanone has a common mechanism of toxicity with othe r substances or how to include this pesticide in a cumulative risk
assessment. Therefore, EPA has not assumed that furanone has a common mechanism of toxicity with other substances and a cumulative risk assessment is not anticipated at this time.

12.0 E NDOCR INE D ISRUPTOR S CREENING P ROGRAM

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessment s of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups.

EPA has developed the Endocrine Disruptor Screening Program ( EDSP ) to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 te sts are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and establish a dose

- response relationshipPage 8 of 12 between the dose and the E, A, or T effect.

Under FFDCA sectio n 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the f irst group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Furanones are not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data call

ins, requiring the submission of EDSP screening assays f or Furanones. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: h ttp://www.epa.gov/endo/

.

13.0 H UMAN S TUDIES

Studies in which adult human subjects were intentionally exposed to furanones to determine their dermal and inhalation exposure haven’t been used to address human health risk assessments on these chemicals.

14.0 D ATA R EQUIREMENTS Data requirements for conventional pesticides will be waived for the furanones based on the afore mentioned characteristics of these chemicals and the end

- use products containing them.

15.0 R EFERENCES

Redden, J. C.

, 09 / 29 / 1995

. The HED C hapter of the Re

- registration Eligibility Decision Document (RED) for Dihydro

- 5

- Pentyl

- 2(3H)

- Furanone (PC Code: 122301) and 5

- Heptyldihydro

- 2(3H)

- Furanone (PC Code: 122302) Case no. 3138: Tanol Derivatives

.
Swe Oo, D 393554

, 09/0 7 /2011

. Tanol derivatives: Review of Human Incidents.

G. F. Kramer, A. Nowotarski, R. Mitkus, D374492, 08/13/2010. D

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

Bar, F. and Griepentrog, F. (1967) Die Situation in der gesun dheitlichen Beurteilung der Aromatisierungsmittel fur Lebensmittel. Medizin Ernahr . 8: 244.

Food Cosmet. Toxicol. Vol. 3, pp. 563

- 569. Pergamon Press 1965.

Food Cosmet Toxicol Vol. 12, pp. 889 and 921. Pergamon Press 1975.

Food and Cosmetics Toxicology Volume 13, 921, 1975Page 9 of 12 Appendix A: Chemistry

1.0 PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION

The two furanones addressed in this document are natural occurring compounds found in apricots and peaches. In addition, dihydro

- 5

- heptyl

- 2(3H)

- furanone is found in milk and meat products, and passion fruit. These are used as fragrance and are registered by the FDA as fo od additives. However, they are not listed as “Generally Recognized as Safe” by the FDA.

1.1 Identification of Active Ingredient

Chemical Name: D ihydro

- 5

- heptyl

- 2(3H)

- furanone Common Name: gamma

- Undecalactone Chemical Type: Repellent PC Code Number: 1 22302 CAS Registry No.: 104

- 67

- 6 Empirical Formula: C 11 H 20 O 2 Molecular Weight: 184.31

Chemical Name: D ihydro

- 5

- pentyl

- 2(3H)

- furanone Common Name: gamma

- Nonalactone Chemical Type: Repellent PC Code Number: 122301 CAS Registry No.: 104

- 61

- 0 Empirical Formula: C 9 H 16 O 2 Molecular Weight: 156.25

1.2 Structural Formula of the Furanones

D ihydro

- 5

- heptyl

- 2(3H)

- furanone D ihydro

- 5

- pentyl

- 2(3H)

- furanonePage 10 of 12 1.3 Physical and Chemical Properties

Chemical Name: D ihydro

- 5

- heptyl

- 2(3H)

- furanone D ihydro

- 5

- pentyl

- 2(3H)

- furanone

Color: colorless to yellow colorless to yellow Odor: strong fruity odor suggestive of peach strong odor suggestive of coconut Melting point: liquid, not applicable liquid, not applicable Solubility: 60% alcohol in water

- 20% soluble 70% alcohol in water

- 33% soluble Insoluble in water 50% alcohol in water

- 20% soluble 60% alcohol in water

- 33% soluble Insoluble in water Stability: stable under all normal conditions stable under all normal conditions Octanol/water partition coefficient: not available not available

Physical state: liquid liquid

Density: 0.942

- 0.945 0.958

- 0.966 Boiling Point not available 243 C Vapor Pressure: not available not available

pH: not available not availablePage 11 of 12 Appendix B : Furanone Products

PRD Appendix A: Food/Feed & Non

– Food/Non

- Feed Uses Considered in Registration Review ( 0 3 / 11 /201 1 ) Partial R eportFood (F) /Non-food (N)

Use Site Formulation Desc ription 1 Application Method/ Type Application Method/ Equipment Product Max App Rate A. I. Max App Rate Max # Apps / Year

Products with F uranones as A ctive I ngredients

N HOUSEHOLD/ DOMESTIC DWELLINGS OUTDOOR PREMISES

66617

- 1 (IMPR) Insecticidal strip treatment Impregnated strip NS NS NS

HUMAN BODY/CLOTHING WHILE BEING WOR N Clothing
treatment Cloth NS NS NS

Skin contact
treatment Ankle band NS NS NS

Skin contact
treatment. Wrist band NS NS NS

N ORNAMENTAL HERBACEOUS PLANTS,Turf 45987

- 1 (G) Spreader Not on label 1 lb/ 100 sq ft 0.104 lb ai / A NS

1 Concentration of the active ingredients: 0.024% dihydro

- 5

- pentyl

- 2(3H)

- furanone and 0.049% dihydro

- 5

- heptyl

- 2(3H)

- furanone.
2 NS = Not SpecifiedPage 12 of 12 

## CONFIDENTIAL APPENDI X

Appendix C: Products containing the furanones as inerts

Two formulations including the furanones as inert ingredients were identified by the Pesticide Reregistration Division, see table below.Food (F) /Non-food (N)

Use Site Formulation Description Application Method/ Type Application Method/ Equipment Product Max App Rate Max # Apps / Year

Products with Furanones as I nactive I ngredients

N Rodspray Fly, Crockroach & Ant Killer 45987

- 2 Spray
treatment Spray NS NS

N Rodspray Indoor

- Outdoor Crawling Insect Killer 45987

- 9 Spray
treatment Spray NS NS
NS = Not Specified