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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS

PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division

Penn A Kem, LLC

Docket Number EPA

‐ HQ

‐ OPP

‐ 2013

‐ 0098

Petition Number 2E8080

Toxcel, on behalf of Penn A Kem, LLC, 3324 Chelsea Avenue, Memphis, TN 38108

, requests to

amend an exemption from the requirement of a tolerance in 40 CFR 180. 1263 for residues of

Tetrahydrofurfuryl Alcohol (THFA)

, (CAS No. 97

‐ 99

‐ 4 ), when used as a pesticide inert ingredient

(solvent/co

‐ solvent ), to include allowance of one herbicide application prior to the preboot

stage to wheat, buckwheat, barley, oats, rye, sorghum, triticale, rice and wild rice; extended use

on canola to the early bolting stage; extended use on soybeans up to the bloom growth stage;

and allowance of use in herbicides with two applications to field corn and pop corn up to 36

inches tall (V8 stage). The petitioner believes no analytical method is needed because it is not

required for the amendment of a tolerance exemption for inert ingredients. Contact: Residue

Chemistry

1. Plant metabolism. Penn A Kem LLC has conducted two GLP plant tissue dissipation/

uptake studies in which three plant species received a foliar treatment with THFA with a 1%

aqueous solution applied at a rate of 100 gallons/acre (equivalent to 8 lb THFA/acre which is

four

‐ fold greater than the maximum anticipated application rate). The first study was

conducted with lettuce, tomato and wheat and demonstrated that THFA concentrations in

treated plants began approaching background levels after 24 hours. THFA ® concentrations in

untreated control plants ranged from <0.22 to 2.9 μ g a.i./g over the course of the study. Final

concentrations of THFA® after 7 days ranged from 1.9 to 3.2 μ g a.i./g (corrected for control

values) for treated plants. The limit of quantitation (LOQ) for the study was 0.278 μg/g, and

treated plants were monitored for seven days after treatment (Gledhill, 2006).

In 2012 a radio

‐ labeled study was completed that monitored treated plants for 27 days

after treatment, and included an analytical method with an LOQ of 0.01 μg/g (Turk, 2012). The

study was conducted with corn, tomato and wheat plants. In this study, concentrations of THFA

had decreased by 98.4%, 92.2% and 97.3% within 24 hours after treatment in corn, tomato and2

wheat plants, respectively, compared to zero hour levels. [ 14 C] THFA concentrations began

approaching background levels after 7 days. [ 14 C]THFA ® concentrations in untreated control

plants ranged from below detection to 0.08 μ g/g (ppm) over the course of the study. Beyond 48

hours, concentrations in treated plants continued to dissipate and approached levels below 0.5

ppm. The low level of radioactivity found in the chromatography of [ 14 C] THFA ® was thought to

be residual radioactivity due to an unknown [ 14 C] component either present in the original

radiochemical stock or generated during the study.

2. Analytical method. NA

‐ Remove (not relevant for exemption request)

3. Magnitude of residues. NA

‐ Remove (not relevant for exemption request)

B. Toxicological Profile

The Agency completed a hazard assessment for THFA in 2006; 1 the results of that assessment

are summarized below.

1. Acute toxicity. Acute toxicity is available for the oral route with an LD 50 for the rat of

1.63

‐ 3.2 g/kg (OECD 2005). THFA was not irritating to the skin of mice (OECD 2005;

Lashmar et al., 1989) but was irritating to the eyes of rabbits (OECD 2005). Acute

dermal, acute inhalation and dermal sensitization data are not available. Some

reports (HSDB 2005) suggest that THFA may be moderately irritating via the dermal

and inhalation routes of exposure to humans.

2. Genotoxicity. THFA is not mutagenic in Salmonella typhimurium or E. coli with or

without exogenous metabolic activation according to a reverse gene mutation assay

(Ames Test) (OECD 2005). In a chromosomal aberration study with Chinese hamster

lung cells (CHL/IU), THFA did not cause structural chromosomal aberration of

polyploidy with or without metabolic activation.

1 “Hazard assessment for the tolerance reassessment of tetrahydrofurfuryl alcohol (THFA)(CAS

Reg. No. 97

‐ 99

‐ 4,” from Elissa Reaves Reregistration Branch 2 Health Effects Division to Pauline

Wagner, Chief, Inert Ingredient Assessment Branch (IIAB), Registration Division. February 21,

2006.3

3. Reproductive and developmental toxicity. An available developmental toxicity study

in rats (MRID 46543102) revealed a quantitative susceptibility based on decreased

fetal body weights and increased incidence of filamentous tail. Subchronic exposure

studies also indicate the potential for alterations in the developing male

reproductive system.

4. Subchronic toxicity. In subchronic studies, males were quantitatively more sensitive

to THFA than females. Consistent decreases in male reproductive organ weights

(testicular, epididyal, and seminal vesicle) were observed in rats in 90

‐ day dietary

(LOAEL=339 mg/kg

‐ day), dermal (LOAEL=300 mg/kg

‐ day), and inhalation (LOAEL <

0.21 mg/L) toxicity studies (MRID 46543103, 46543104, and 46543105,

respectively). A 90

‐ day oral (dietary) study in dogs (OECD 2005) revealed decreased

testes weights of males in all treated groups (approximately 25, 75, and 150

mg/kg/day) compared to controls, with severe testicular atrophy in all males at the

highest dose. Decreased spermatogenic activity was noted in males of the 75

mg/kg/day group, and was interepreted as a prodromal sign of atrophy. A 28

‐ day

repeated oral (gavage) study in rats (OECD 2005) revealed significant decreases in

absolute testes and epididymal weights after 28 days of 600 mg/kg/day that

continued through the 14

‐ day recovery period. Necrosis of the seminiferous tubular

epithelium of the testes was also observed in males of the 150 and 600 mg/kg/day

group at 28 days. Necrosis of the testes was also observed in males of the 600

mg/kg/day group at the end of the 14

‐ day recovery period.

5. Chronic toxicity. No chronic toxicity or cancer studies are available for THFA

However, mutagenicity studies indicate that THFA is not mutagenic in Salmonella

typhimurium or E. coli with or without metabolic activation. THFA was also negative

for causing structural chromosomal aberrations or polyploidy with our without

metabolic activation in cultured Chinese hamster lung cells (OECD 2005).

6. Animal metabolism. No animal metabolism studies are available for THFA.

7. Metabolite toxicology

. NA

‐ REMOVE

8. Endocrine disruption

. Alterations in pituitary, thymus, adrenal and thyroid weights

have been reported after subchronic exposure (28

‐ days) to 600 mg/kg/day in male rats and

pituitary weights at 150 mg/kg/day in female rats (OECD 2005). Decreased absolute and relative

adrenal weights were observed in males and females receiving 5000 ppm (approximately 3394

mg/kg/day males and 401 mg/kg/day females) or 10,000 ppm (equivalent to 673 and 781

mg/kg/day males and females, respectively) of the 90

‐ day oral toxicity study in rats. The

decreased absolute adrenal weights were also observed in male rats receiving 1000 mg/kg/day

of the 90

‐ day dermal toxicity study.

A summary of the toxicological endpoints for THFA established by US EPA (2006) and used for

human risk assessment is shown in the following Table 1.

Table 1

‐‐ Summary of Toxicological Doses and Endpoints for THFA for Use in Human Health Risk

Assessment



### Exposure/Scenario Point

Departure/Uncertainty

Safety Factors RfD/Level of Concern

Risk Assessment Study and Toxicolog

Effects

Acute Dietary

(Females 13-49 yrs ) NOAEL=50 mg/kg/da y

UFH=10x

UFA=10x

UFDB=10x

FQPASF=1 aRfD=0.05 mg/kg/day

aPAD=0.05 mg/kg/day

LOC=1000 Developmental, rat

LOAEL 100 mg/kg/ d

b ased on decreased f

b ody weight and incre a

incidence of filamen t

tail, complete resorption

500 and 1000 mg/kg/day

Acute Dietary (gen e

populations, inclu d

infants and childre n Utilized the NOAEL f r

the rat developme n

Study 1000 Utilized the NOAEL f r

the rat developmental St u

Chronic dietary (

populations) NOAEL=69 mg/kg/da y

UFH=10x

UFA=10x

UFDB=10x

FQPASF=1 aRfD=0.069 mg/kg/da y

aPAD=0.069 mg/kg/da y 90-day oral, rat

LOAEL=339 and 4

mg/kg /day in males

females, respectively.

FQPA SF = Food Quality Protection Act Safety Factor. LOAEL = lowest-observed-adverseeffect-level. LOC = level of concern. mg/kg/day = milligram/kilogram/day. MOE = margin

of exposure. NOAEL = no-observed- adverse-effect- level. PAD = population adjusted dose (a

= acute,

c = chronic). RfD = reference dose. UF = un certainty factor. UFA = extrapolation from

animal to human (interspecies). UFDB = to a ccount for the absence of data or other data

deficiency.

UFH = potential variation in sensitivity among members of the human population

(intraspecies). BW = Body wei ght. BWG = Body weight gain.

A. Aggregate Exposure

1. Dietary exposure. Dietary exposure to THFA in food was assessed using the new

DEEM

‐ FCID model version 3.14 that contains food consumption information from the U.S.

Department of Agriculture (USDA) NHANES 2

‐ day data for 2003

‐ 2008. Detectable residues are5

not anticipated to be present in food or feed made from cereal grains, soybeans, canola or

cottonseed treated post

‐ emergence because the restrictions in the proposed exemption

regulation limit the use of THFA to products that are applied before edible portions are formed

and because there is a long period between application and harvest. In addition, THFA is volatile

and will dissipate in the presence of heat during food processing/manufacturing and during

home preparation.

The “worst

‐ case” exposure analysis includes all food forms of all commodities permitted

to be treated post

‐ emergence (cereal grains, soybean, cottonseed, and canola) with the

conservative assumption that all food

‐ forms contain 0.51 ppm based on the results of the 2011

plant uptake study, which was conducted at 4X the maximum anticipated use rate for THFA. The

residue value of 0.51 ppm represents the highest THFA value observed 27 days after the 4X

treatement, however, according to the author of the 2011 plant uptake study, it was not

possible to determine whether the residue consisted of THFA or an unknown [ 14 C] component

either present in the original radiochemical stock or generated during the study. During the

tolerance exemption reassessment for THFA, EPA determined that existing pre

‐ plant and pre

‐

emergence uses of THFA meet the Agency’s safety requirements, considering THFA’s physical

‐

chemical properties and biodegradation potential in the environment (71 Fed Reg p.45412).

Estimated exposure was compared to the toxicological endpoints developed by EPA (see

Table 1, above). The chronic dietary RfD is 0.069 mg/kg

‐ BW/day based on the NOAEL of 69

mg/kg

‐ BW/day from the 90

‐ day oral subchronic toxicity study in the rat with a 100X safety

factor for intra

‐ and interspecies variability and an additional 10X for database uncertainty

because a subchronic study was used for chronic toxicity. The acute dietary RfD is 0.05 mg/kg

‐ BW/day based on the NOAEL of 50 mg/kg

‐ BW/day from the developmental study in the rat with

a 100X safety factor for intra

‐ and interspecies variability and an additional 10X for database

uncertainty. Although an FQPA safety factor of 10 was retained at 10X, in order to avoid double

counting EPA determined that the application of a 10X database uncertainty factor to account

for missing studies replaced the FQPA 10X safety factor for THFA (US EPA, 2006).

The model included the conservative assumption that 100 percent of all cereal grains,

soybean and cotton would be treated, and that 0.51 ppm THFA would be present on all food

forms. In addition, the model scenarios assume that processing would not reduce potential

residues in processed foods (e.g., flour, cottonseed oil).

i. Food.

Chronic dietary exposure

. Exposure to all population groups was very low, with Children

1

‐ 2 yrs having the greatest exposure of 0.005043 mg/kg

‐ BW/day representing 7.3% of the6

chronic RfD of 0.069 mg/kg

‐ BW/day. Exposure to the overall U.S. Population was 0.002080

mg/kg

‐ BW/day, representing 3.0% of the chronic RfD.

Acute dietary exposure

. The 99 th percentile exposure is evaluated for unrefined

exposure analyses. The most highly exposed group was Children 1

‐ 2 yrs at 0.015616 mg/kg

‐ BW/day, representing 31% of the acute RfD of 0.05 mg/kg

‐ BW/day and a Margin of Exposure

(MOE) of 3,201 (with an MOE of less than 1,000 being the Level of Concern). Exposure to the

U.S. Population was 0.008264 mg/kg

‐ BW/day, representing 17% of the acute RfD and an MOE of

6,050.



### Population Group Exposure (mg/kg-BW/day)

Chronic Dietary Exposure and Risk:

NOAEL = 69 mg/kg-BW/day; cRfD=0.069 mg/kg-BW/day

U.S. Population 0.002080 3.0% of cRfD

Children 1-2 years 0.005043 7.3% of cRfD

Acute Dietary Exposure and Risk:

NOAEL=50 mg/kg-BW/day; aRfD=0.05 mg/kg- BW/day; Level of Concern (LOC)=1000

U.S. Population 0.008264 MOE=6,050; 17% of aRfD

Children 1-2 years 0.015616 MOE=3,201; 31% of aRfD

ii. Drinking water. Contributions to surface/drinking water are not anticipated

from the use of THFA

‐ containing pesticide products under the proposed use

limitations, considering THFA’s physical

‐ chemical properties and biodegradation

potential in the environment.

2. Non

‐ dietary exposure

. No residential risks have been identified for existing uses of

THFA; the proposed expanded uses on cereal grains, canola and soybeans do not pose any

residential risks.

D. Cumulative Effects

A cumulative exposure assessment is not required because EPA has determined that

THFA does not have a common mechanism of toxicity with any other chemical (71 FR p. 18691,

April 12, 2006).7

E. Safety Determination

1. U.S. population. The results of the conservative, screening level chronic and acute

risk assessments for THFA demonstrate that that there is a reasonable certainty that no harm

will result to the U.S. population from the proposed expansion of the exemption regulation for

THFA.

2. Infants and children

. The results of the conservative, screening level chronic and acute

risk assessments for THFA demonstrate that that there is a reasonable certainty that no harm

will result to infants or children from the proposed expansion of the exemption regulation for

THFA.

F. International Tolerances NA

‐ Remove



### References:

Chengelis, C.P. (1993) 13-Week Dietary Toxici ty Study in Rats with THFA. WIL Research

Laboratories, Ashland, OH Project No. WIL-12255. July 1, 1993. Unpublished.

MRID 46543103

Hazardous Substances Database (HSDB) (20 05). Tetrahydrofurfural Alcohol (THFA).

CASRN:97-994 http://toxnet.nlm.nih.gov

Gledhill, W. E. (2006) Plant Tissue Dissipation /Uptake of Tetrahydrofurfuryl Alcohol

(THFA®). Springborn Smithers Laboratorie s, Wareham, Massachusetts. August 7,

2006. Lab Project ID: Springborn Smithers Study No. 13869.6101.

MRID 47060101

Lashmar UT, Hadgraft J, and Thomas N. (1989) Topical application of penetration enhancers

to the skin of nude mice: a histological study. J. Pharm Pharmacol. 41 (2): 118-122.

Nemec, Mark D. 2000. Five day oral toxicity study of tetrahydrofurfuryl alcholo (THFA) in

female rabbits. WIL Research Laborator ies, Ashland, OH Pr oject No. WIL-12266.

March 1, 2000. Unpublished. MRID 46543101

Nemec, Mark D. (1994) A dose range-fi nding developmental toxicity study of

tetrahydrofurfural alcohol (THFA) in rats. WIL Research Laborat ories, Ashland, OH

Project No. WIL-12292. February 14, 1994. Unpublished. MRID 46543102

OECD (2005) IUCLID Dataset for 2-Furanm ethanol, tetradhydro-. CAS No. 97-99-4.

http://www.oecd.org/dataoecd/158/35286232.pdf as referenced on OECDs Integrated

High Production Voume (HP) Database: http://cs3hq.oecd.org/scripts/hpv/8



### Turk, R. S. (2012). Plant Tissue Dissipation/Up take of Tetrahydrofurfuryl Alcohol (THFA®).

Smithers Viscient, Wareham, Massachusetts . March 5, 2012. Project ID: Springborn

Smithers Study No. 13869.6102.

Ulrich, C.E. (1998) A 90-Day dermal toxici ty study of THFA in rats. WIL Research

laboratories, Inc., Ashland Ohio. Project No. WIL-1 44031. June 1, 1998.

Unpublished. MRID 46543104

Ulrich, C.E. (1998) A 90-Day inhalation toxici ty study of THFA in rats. WIL Research

laboratories, Inc., Ashland Ohio. Project No. WIL-144032. June 30, 1998.

Unpublished. MRID 46543105

US EPA (2006) “Hazard assessment for the tole rance reassessment of tetrahydrofurfuryl

alcohol (THFA)(CAS Reg. No. 97-99-4,” from Elissa Reaves Reregistration Branch 2

Health Effects Division to Pauline Wagner, Ch ief, Inert Ingredient Assessment Branch

(IIAB), Registration Division. February 21, 2006.