Document ID: EPA-HQ-OPP-2013-0098-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-02-27T05:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  
EPA Registration Division contact: [Janet Whitehurst (703) 305-6129]

Penn A Kem, LLC

Docket Number EPA-HQ-OPP-2013-0098

Petition Number 2E8080

	EPA has received a pesticide petition 2E8080 from Penn A Kem, LLC,  3324 Chelsea Avenue, Memphis, TN 38108, proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR Part 180.1263, the exemption from the requirement of a tolerance for Tetrahydrofurfuryl Alcohol (THFA), CAS Reg. No. 97-99-4, by allowing one pre-boot herbicide application to all small cereal grains, and by extending use on canola to early bolting stage, and use on soybeans to bloom stage.  EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of  FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data support granting of the petition. Additional data may be needed before EPA rules on the petition.

   A. 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[(R)] concentrations in untreated control plants ranged from <0.22 to 2.9 μg a.i./g over the course of the study.  Final concentrations of THFA(R) after 7 days ranged from 1.9 to 3.2 μg a.i./g (corrected for control values) for treated plants.  The limit of quantitation (LOQ) for the study was 0.278 ug/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 ug/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 and wheat plants, respectively, compared to zero hour levels.  [[14]C] THFA concentrations began approaching background levels after 7 days.  [[14]C]THFA[(R)] concentrations in untreated control plants ranged from below detection to 0.08 μg/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[(R)] 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; the results of that assessment are summarized below.

      1. Acute toxicity. Acute toxicity is available for the oral route with an LD50 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.  
         
      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 339 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 of Departure/Uncertainty Safety Factors
RfD/Level of Concern for Risk Assessment
Study and Toxicological Effects
Acute Dietary 
(Females 13-49 yrs)
NOAEL=50 mg/kg/day
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/day, based on decreased fetal body weight and increased incidence of filamentous tail, complete resorptions at 500 and 1000 mg/kg/day
Acute Dietary (general populations, including infants and children)
Utilized the NOAEL from the rat developmental Study

1000
Utilized the NOAEL from the rat developmental Study

Chronic dietary (All populations)
NOAEL=69 mg/kg/day
UFH=10x
UFA=10x
UFDB=10x
FQPASF=1
aRfD=0.069 mg/kg/day
aPAD=0.069 mg/kg/day

90-day oral, rat
LOAEL=339 and 401 mg/kg /day in males and females, respectively.
FQPA SF = Food Quality Protection Act Safety Factor. LOAEL = lowest-observed-adverse-effect-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 = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFDB = to account for the absence of data or other data deficiency. 
UFH = potential variation in sensitivity among members of the human population (intraspecies). BW = Body weight. BWG = Body weight gain.

   B. 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 are 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 the 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).

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 Toxicity Study in Rats with THFA. WIL Research Laboratories, Ashland, OH  Project No. WIL-12255.  July 1, 1993. Unpublished.  MRID 46543103

Hazardous Substances Database (HSDB) (2005).  Tetrahydrofurfural Alcohol (THFA). CASRN:97-994  http://toxnet.nlm.nih.gov

Gledhill, W. E. (2006) Plant Tissue Dissipation /Uptake of Tetrahydrofurfuryl Alcohol (THFA(R)).  Springborn Smithers Laboratories, 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 Laboratories, Ashland, OH  Project No. WIL-12266.  March 1, 2000. Unpublished.  MRID 46543101

Nemec, Mark D. (1994) A dose range-finding developmental toxicity study of tetrahydrofurfural alcohol (THFA) in rats.  WIL Research Laboratories, Ashland, OH  Project No. WIL-12292.  February 14, 1994. Unpublished.  MRID 46543102

OECD (2005) IUCLID Dataset for 2-Furanmethanol, 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/

Turk, R. S. (2012).  Plant Tissue Dissipation/Uptake of Tetrahydrofurfuryl Alcohol (THFA(R)).  Smithers Viscient, Wareham, Massachusetts.  March 5, 2012.  Project ID: Springborn Smithers Study No. 13869.6102.

Ulrich, C.E.  (1998) A 90-Day dermal toxicity study of THFA in rats. WIL Research laboratories, Inc., Ashland Ohio.  Project No. WIL-144031.  June 1, 1998. Unpublished.  MRID 46543104

Ulrich, C.E.  (1998) A 90-Day inhalation toxicity 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 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.