Document ID: EPA-HQ-OPP-2012-0309-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-07-25T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: Laura Nollen, (703) 305-7390

Interregional Research Project Number 4 (IR-4)

Petition Number (PP#) 2E8013

	EPA has received a pesticide petition, PP# 2E8013, from Interregional Research Project Number 4 (IR-4), IR-4 Project Headquarters, Rutgers, The State University of New Jersey, 500 College Road, East, Suite 201, W, Princeton, NJ  08540 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 180.431 by establishing a tolerance for residues of clopyralid: (3,6-dichloro-2-pyrindinecarboxylic acid) in or on the raw agricultural commodities teff, forage at 9.0 parts per million (ppm); teff, grain at 3.0 ppm; teff, straw at 9.0 ppm; and teff, hay at 9.0 ppm.  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 supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

	1. Plant metabolism. [The Agency has previously concluded that the nature of the residue in plants and animals is adequately understood.  Additionally the Agency has determined that tolerances should be comprised of the parent compound only as no metabolites of toxicological significance were detected in metabolism studies.]

	2. Analytical method. [An adequate analytical method is available for enforcement of the tolerance expression in or on food.  Dow AgroSciences Method No. ACR 79.5 can be utilized to determine residues of clopyralid in teff in support of the proposed tolerance.  This method determines clopyralid as the methyl ester by gas chromatography using electron capture detection.  This method has been successfully validated by EPA and has been published in FDA's Pesticide Analytical Manual, Volume II (PAM II).]

	3. Magnitude of residues. Teff has been proposed and validated for crop group 15 Cereal Grains at the 2002 IR-4 / USDA International Crop Grouping Symposium, and is scheduled to be included in a crop group submission to the EPA..  The label rate for clopyralid on wheat is the same as the proposed label for teff.  Based on the existing residue tolerances for clopyralid (40 CFR 180.431) on wheat, IR-4 proposes that EPA establish a tolerance for clopyralid in or on teff. 

The nature of the residues of clopyralid is adequately understood, and an acceptable analytical method is available for enforcement purposes.]  

B. Toxicological Profile

	1. Acute toxicity.  [For acute risk assessments, EPA has established an acute reference dose (aRfD) of 0.75 mg/kg/day for all population sub-groups including infants and children.  The aRfD is based on the developmental toxicity study on rats with a NOAEL of 75 mg/kg/day and uncertainty factor of 100 accounting for both interspecies extrapolation (10x) and intraspecies variability (10x).  A decrease in weight gain was observed during gestation of 6-9 days at a maternal LOAEL of 250 mg/kg/day.  EPA determined that an additional factor to protect infants and children was not appropriate.  

Clopyralid has low acute toxicity.  The rat oral LD50 is 5,000 mg/kg or greater for males and females.  The rabbit dermal LD50 is >2,000 mg/kg and the rat inhalation LC50 is >1.0 mg/L air (the highest attainable concentration).  In addition, clopyralid is not a skin sensitizer in guinea pigs and is not a dermal irritant in rabbits.  Technical clopyralid is an ocular irritant, but ocular exposure to the technical material would not normally be expected to occur to infants or children or the general public.  End use formulations of clopyralid have similar low acute toxicity profiles and most have low ocular toxicity as well.]

	2. Genotoxicty. [Clopyralid is not genotoxic.  The following in vitro and in vivo studies have been conducted and all were negative for genotoxic responses:  Ames bacterial mutagenicity assay (with and without exogenous metabolic activation); Host-Mediated assay In vivo cytogenetic test, rat; In vivo cytogenetic test, mouse; In vivo dominant lethal test, rat; In vitro unscheduled DNA synthesis assay in primary rat hepatocyte cultures; In vitro mammalian cell gene mutations assay in Chinese hamster ovary cell cultures (with and without exogenous metabolic activation).]

	3. Reproductive and developmental toxicity. [Developmental toxicity was studied using rats and rabbits.  The developmental study in rats resulted in a developmental NOEL of >250 mg/kg/day (a maternally toxic dose) and a maternal toxicity NOEL of 75 mg/kg/day.  A 1974 study in rabbits revealed no evidence of developmental or maternal toxicity at 250 mg/kg/day; thus, the developmental and maternal NOEL was >250 mg/kg/day.  A more recent study in rabbits (1990) resulted in developmental and maternal NOELs of 110 mg/kg/day based on maternal toxicity at 250 mg/kg/day.  Based on all of the data for clopyralid, there is no evidence of developmental toxicity at dose levels that do not result in maternal toxicity.  In a 2-generation reproduction study in rats, pups from the high dose group which were fed diets containing clopyralid had a slight reduction in body weight during lactation and an increase in liver weights in F1a and F1b weanlings.  The NOEL for parental systemic toxicity was 500 mg/kg/day.  There was no effect on reproductive parameters at >1,500 mg/kg/day nor was there an adverse effect on the morphology, growth or viability of the offspring; thus, the reproductive NOEL is >1,500 mg/kg/day.]

	4. Subchronic toxicity. [The following studies have been conducted using clopyralid.  In a rat 90-day feeding study, Fischer 344 rats were fed diets containing clopyralid at doses of 5, 15, 50 or 150 mg/kg/day with no adverse effects attributed to treatment.  In a second study, Fischer 344 rats were fed diets containing clopyralid at doses of 300, 1,500 and 2,500 mg/kg/day.  Effects at the highest doses were decreased food consumption accompanied by decreased body weights and weight gains in both males and females.  Slightly increased mean relative liver and kidney weights were noted in males of all doses and in females at the top 2 doses.  Because there were no other effects, the kidney and liver weight effects were judged as being adaptive rather than directly toxic.  The no-observed-adverse-effect level (NOAEL) was 1,500 mg/kg/day for males and females.  The no-observed-effect level (NOEL) was 300 mg/kg/day for females.  In a mouse 90-day feeding study, B6C3F1 mice were fed diets containing clopyralid at doses of 200, 750, 2,000 or 5,000 mg/kg/day.  A slight decrease in body weight occurred at the top dose in both sexes.  The liver was identified as the target organ based on slight increases in liver weights and minimal microscopic alterations at the higher dose levels.  The liver changes were considered to be reversible and adaptive.  The NOEL for males was 2,000 mg/kg/day and for females was 750 mg/kg/day.  In a 180-day feeding study, beagle dogs were fed diets containing clopyralid at doses of 15, 50 or 150 mg/kg/day; there were no adverse effects.  In a second dietary study, dogs also were fed diets containing clopyralid at doses of 15, 50 or 150 mg/kg/day; the only effect was an increase in the mean relative liver weight in females at the 150 mg/kg/day.  In a 21-day dermal study, clopyralid was applied by repeated dermal application to New Zealand White rabbits at dose levels up to 1,000 mg/kg/day.  Treatment produced no systemic effects.]

	5. Chronic toxicity. [For chronic dietary risk assessments, EPA has established a chronic reference dose (cRfD) of 0.15 mg/kg/day for all population sub-groups.  The cRfD is based on the 2-year combined chronic feeding-carcinogencity study in rats with a NOAEL of 15 mg/kg/day and uncertainty factor of 100 accounting for both interspecies extrapolation (10x) and intraspecies variability (10x).  An increase in epithelial hyperplasia and thickening of the limiting ridge of the stomach was observed in both sexes with a LOAEL of 150 mg/kg/day.  No tumorigenic response was present.  EPA determined that an additional factor to protect infants and children was not appropriate. 

Clopyralid has been classified as "not likely" to be a human carcinogen based on no evidence of carcinogencity in rats and mice and no evidence of genotoxicity in an acceptable mutagenicity studies.  Thus, an exposure assessment to address cancer risk is not required.]

	6. Animal metabolism. [Disposition and metabolism of clopyralid were tested in male and female rats at a dose of 5 mg/kg (oral).  The majority of a radioactive dose was excreted in 24 hours of all dose groups through urine.  Fecal elimination was minor.  Detectable levels of residual radioactivity were observed in the carcass and stomach at 72 hours post-dose.  HPLC and TLC analysis of urine and fecal extracts showed no apparent metabolism of clopyralid. 

Following oral administration, clopyralid was rapidly and completely eliminated from goats, chickens and sheep.  In goats and sheep, the majority of the administered dose was excreted in the urine.  This residue was found to be mostly unchanged clopyralid, and in goats, the remainder was found to be a glycine conjugate of clopyralid.  Residues in milk were low, reaching a plateau of 0.03-0.05 mg/kg after 3-4 days.  Radioactivity levels in milk fat were below the limit of detection, indicating that there is no tendency for clopyralid to accumulate in milk fat.  Tissue residue levels were also low and comprised unchanged clopyralid only.  The residues in the eggs and chicken tissues were unchanged clopyralid.  Based on the ruminant and poultry nature of residue (NOR) studies, the residue definition for animal tissue is clopyralid, the parent compound. 

In animal feeding studies, calves fed clopyralid at levels as high as 1,000 ppm showed no ill, effects due to ingestion of the chemical.  Additionally, no difference is observed between the control and treated groups in weight gain and feed consumption.  After withdrawal from treated feed, residues in all tissues diminished rapidly from the levels found after feeding clopyralid at 1,000 ppm for 28 days.  At the levels of herbicide that would be expected in grains used at cattle feed, no residues would occur above the 0.05 ppm level.]

	7. Metabolite toxicology. [Following oral administration in the rat, clopyralid was rapidly and completely (>80%) absorbed and excreted quantitatively unchanged in the urine.  There were no differences in distribution of radioactivity between dose rates, sex, route (oral vs. iv) or frequency of administration.  Clopyralid was not metabolized in the rat.  The Residue of Concern (ROC) in plant and animal products is the parent compound, clopyralid.]

	8. Endocrine disruption. [There is no evidence to suggest that clopyralid has an effect on the endocrine system.]

C. Aggregate Exposure

	1. Dietary exposure. [Dietary exposure to US-general population and sensitive population subgroups was assessed from all clopyralid currently listed uses, plus the newly proposed use on teff.  Water from direct and indirect exposure was also included in the dietary exposure and risk assessment.]

	i. Food. [Tolerances are established for residues of the herbicide, clopyralid (3,6-dichloro-2-pyridinecarboxylic acid) in or on the raw agricultural commodities and are published in 40 CFR Section 180.431.  Parent clopyralid, only, is the residue definition in animal and plant commodities.  Tolerances have been proposed for the residues of clopyralid in teff.  These proposed tolerances are adequate to cover the highest expected field residues from the labeled use of clopyralid.  

In conducting the acute and chronic dietary assessments, Dow AgroSciences used the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID, Version 2.0) which incorporates food consumption data as reported in the CSFII Survey 1994-1996 and 1998.  A conservative analysis (Tier 1) was performed with the assumptions that 100% of crops with approved and proposed uses of clopyralid including those proposed by petition in 2011 but not yet approved [Apple; raw and processed commodities, Rapeseed Subgroup 20A except camelina (gold of pleasure), Leafy Brassica Greens subgroup 5B] and additionally teff would be treated with the pesticide and that the residues would be present at the tolerance levels. 

Based on these conservative assumptions and using an aRfD of 0.75 mg/kg/day, for the U.S. general population, the Tier I acute dietary exposure at the 95th percentile from food to clopyralid was estimated to be 0.034 mg/kg/day, or 4.6% of the aPAD for the U.S. population; and 0.070 mg/kg/day, which represents 9.3% of the aPAD for children (1-2 years), the population sub-group predicted to be potentially most exposed.  Adverse effects are not expected for exposures utilizing <100% of the aPAD, therefore, acute dietary exposure and risk for the general U.S. population and children are well within the acceptable levels. 

Based on these conservative assumptions and using an cRfD of 0.15 mg/kg/day, for the U.S. general population, the Tier I chronic dietary exposure from food to clopyralid was estimated to be 0.013 mg/kg/day, or 8.7 % of the cPAD for the U.S. population; and 0.035 mg/kg/day, or 23.6 % of the cPAD for children (1-2 years), the population sub-group predicted to be potentially most exposed.  Adverse effects are not expected for exposures utilizing <100% of the cPAD, therefore, chronic dietary exposure and risk for the general U.S. population and children are well within the acceptable levels. 
In summary, the currently proposed use for teff does not alter the dietary burden via dietary exposure nor alter the proposed risk assessment determinations submitted in 2011]
	ii. Drinking water. [Since the Agency lacks sufficient monitoring data to complete a comprehensive exposure and risk assessment for florasulam in drinking water, drinking water concentration estimates are made on simulation taking into account data on the physical characteristics of clopyralid.  

Guidance from EPA has indicated that Tier 1 screening level models, such as FIRST (FQPA Index Reservoir Screening Tool), and SCI-GROW, maybe used to estimate upper-bound pesticide residues in surface water and ground water when assessing potential exposure through drinking water. 

FIRST is an extremely conservative estimate for predicting surface water concentrations, and considers adsorption of the pesticide to soil or sediment, incorporation of the pesticide at application, direct deposition of spray drift into the water body, and degradation of the pesticide in soil before runoff and within the water body.  

In an assessment published in Federal Register: March 24, 2010 (Volume 75, Number 56), FRL-8814-2], EPA used FIRST and SCI-GROW models to estimate the environmental concentration (EEC) for surface water and ground water, respectively.  The EECs of clopyralid estimated by EPA for ground water is 0.39 parts per billion (ppb) for both acute and chronic exposures.  The EECs for surface water were estimated to be 45 ppb for acute exposure and 11.9 ppb for chronic exposure.

Estimated environmental concentrations (EEC) of pesticide in surface water were then inputted into DEEM model for estimation of dietary exposure from water both direct and indirect sources.  The input of water residues along with food into the DEEM model provides a conservative estimate of the total exposure from food and water sources.

When water exposure was aggregated with food, acute dietary exposure was 9.5 % of the aPAD for children 1-2 years, the most highly exposed population sub-group.  Additionally, chronic dietary exposure was 23.8 % of the cPAD for children 1-2 years, the most highly exposed population sub-group.  Therefore, aggregate exposure to clopyralid in drinking water would not result in unacceptable levels of human health risk.]

	2. Non-dietary exposure. [Clopyralid is no longer registered for residential turf uses that would result in residential exposure.  Thus, the risk from non-dietary exposure is considered negligible.]

D. Cumulative Effects

	[Currently, no methodologies are available to resolve the complex scientific issues concerning common mechanism of toxicity and cumulative exposure and risk.  The U.S. EPA has begun a pilot process to study this issue further through the examination of particular classes of pesticides.  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, clopyralid does not appear to produce a toxic metabolite produced by other substances. For the purposes of this notice, therefore, EPA has not assumed that clopyralid has a common mechanism of toxicity with other substances.  As such, Dow AgroSciences believes it is appropriate to consider only the potential risks of clopyralid in this exposure assessment.]

E. Safety Determination

	1. U.S. population. [Using the conservative exposure assumptions (Tier I) described above, and based on the completeness and reliability of the toxicity data, the aggregate exposure (food and water only) to clopyralid on registered uses as well as the proposed uses, as determined under the guidance of the FQPA, will utilize 4.7% of the aPAD for the U.S. population and 2.9% of the aPAD for females 13-49 years old.  The aggregate exposure (food and water only) to clopyralid, on registered uses as well as the proposed uses as determined under the guidance of the FQPA, will utilize 8.9% of the cPAD from the dietary exposure for the U.S. population, and 6.5% of the cPAD for females 13-49 years old.  The calculated exposure was greatest from water as estimated by FIRST surface water modeling.  Generally, and under the FQPA, the U.S. EPA has no concern for exposures below 100% of the cPAD.  Therefore, there is a reasonable certainty that no harm will result to the general U.S. population from aggregate exposure to clopyralid residues from the approved and proposed uses.]

	2. Infants and children. [In assessing the potential for additional sensitivity of infants and children to residues of clopyralid, data from developmental toxicity studies in rats and rabbits and a multi-generation reproduction study in the rat are considered.  The developmental toxicity studies are designed to evaluate adverse effects on the developing organism resulting from pesticide exposure during prenatal development.  Reproduction studies provide information relating to effects from exposure of both parents to the pesticide on the reproductive capability and potential systemic toxicity of mating animals and on various parameters associated with the well being of offspring.  There was no effect on reproductive parameters at >1,500 mg/kg/day nor was there an adverse effect on the morphology, growth or viability of the offspring.  

FFDCA section 408 provides that the U.S. EPA may apply an additional safety factor for infants and children in the case of threshold effects to account for pre- and post-natal toxicity and the completeness of the database.  Based on the current toxicological data requirements, the database for clopyralid relative to pre- and post-natal effects for children is complete.

The EPA determined that an additional FQPA factor to protect infants and children is not required for clopyralid as there is no indication of increased sensitivity of infants and children relative to adults.

Thus, based on the completeness and reliability of the toxicity data and the conservative exposure assessment, the aggregate exposure (food and water only) to clopyralid, as determined under the guidance of the FQPA, will utilize 9.5 % of the aPAD and 23.8 % of the cPAD from the dietary exposure for the most sensitive population sub-group, children 1-2 years old.  It is concluded then that there is a reasonable certainty that no harm will result to infants and children from acute- and chronic-term aggregate exposures to clopyralid residues from the approved and proposed uses.]

F. International Tolerances

	[There are no Codex, Canadian or Mexican Maximum Residue limits (MRLs) for residues of clopyralid in or on the requested commodities.  International harmonization is therefore not an issue for this notification.]