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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE 

PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

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

Petition Number 1E7882

EPA has received a pesticide petition, PP# 1E7882, 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 

commodity apple at 0.05 parts per million (ppm); brassica, leafy greens, subgroup 5B at 

5.0 ppm; rapeseed subgroup 20A, except gold of pleasure, seed at 3.0 ppm; rapeseed 

subgroup 20A, except gold of pleasure, meal at 6.0 ppm; rapeseed subgroup 20A, except 

gold of pleasure, forage at 3.0 ppm. Upon the approval of the aforementioned tolerances, 

IR-4 additionally proposes to remove established tolerances for residues of the herbicide, 

clopyralid, in or on the following raw agricultural commodities: canola, seed at 3.0 ppm; 

canola, meal at 6.0 ppm; flax, seed at 3.0 ppm; flax, meal at 6.0 ppm; rapeseed, seed at 

3.0 ppm; rapeseed, forage at 3.0 ppm; and mustard greens at 5.0 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. Apple: An adequate analytical method is available for 

enforcement of the tolerance expression in or on food. Dow AgroSciences Method No. 

ACR 79.5 was utilized to determine residues of clopyralid in apples, fruits and apple 

fractions 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).
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3. Magnitude of residues. Apple: IR-4 has conducted a magnitude of residue study

for clopyralid in/on apple. Data were collected from twelve field trials conducted over 

two years in the major apple growing regions of the U.S.

At each trial, a single orchard floor broadcast application of the test substance was made 

to the treated plot 28 to 30 days before harvest. The application rate was 0.25 lb acid 

equivalent (a.e.)/A. The applications were made using appropriate spray equipment, and 

the spray volume was sufficient to provide adequate dispersal of the test substance. 

Samples were harvested 28 to 30 days after the application. 

No detectable residues were found in the treated or untreated apple fruit, or apple juice. 

There was no concentration of the clopyralid residues in apple pomace processed 

fractions. These data demonstrate that clopyralid applied to pome fruit in accordance 

with the proposed use directions will not result in residues exceeding the proposed 

tolerance.

Leafy Brassica Greens Subgroup 5B: Proposed is using the clopyralid tolerance on 

mustard greens at 5.0 ppm as surrogate data to support tolerance on Leafy Brassica 

Greens subgroup 5B. As per EPA CFR 180.41(Crop group tables) mustard greens is 

representative commodity for Leafy Brassica Greens subgroup 5B. 

Rapeseed Subgroup 20A, except camelina (gold of pleasure): Clopyralid has tolerances 

for canola for meal and seed at 6.0 ppm and 3.0 ppm, respectively. The final rule for 

revision to the new Oilseed crop group 20 was published in Federal Register/Vol.75, 

No.235, on December 8, 2010. All of the members in the Rapeseed subgroup 20A can 

obtain a tolerance based on rapeseed. Canola is the primary type of rapeseed grown in 

the United States.

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 
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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); HostMediated 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 
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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.
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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 apple orchards, Rapeseed Subgroup 20A except camelina (gold of 

pleasure), and Leafy Brassica Greens Subgroup 5B. 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 or on apple, raw and processed commodities at 0.05 ppm. Additional 

tolerances are proposed for Rapeseed Subgroup 20A except camelina (gold of pleasure), 

and Leafy Brassica Greens Subgroup 5B. 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 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 
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0.035 mg/kg/day, or 23.6 % of the cPAD for children (1-2 years), the population subgroup 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.

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. 
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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.
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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.