UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

	OFFICE OF PREVENTION, PESTICIDES

	AND TOXIC SUBSTANCES

  SEQ CHAPTER \h \r 1 MEMORANDUM

DATE:  	01-OCT-2008

SUBJECT:	4-(4-chloro-2-methylphenoxy)butanoic acid (MCPB); Human-Health Risk Risk Assessment for Proposed Section 3 New Use on Mint.

PC Code:  019201	DP Barcode:  D343743

Decision No.:  383254	Registration No.:  71368-5

Petition No.:  7E7257	Regulatory Action:  Section 3 Registration

Risk Assessment Type:  Single Chemical/Aggregate	Case No.:  2365

TXR No.:  NA	CAS No.:  94-81-5

MRID No.:  NA	40 CFR:  §180.318

		              									Ver.Apr.08

FROM:	Sarah J. Levy, Chemist

		Lisa Austin, Ph.D., Toxicologist

Mary Clock-Rust, Biologist

		Registration Action Branch 1 (RAB1)

Health Effects Division (HED; 7509P)

THROUGH:	Dana Vogel, Branch Chief

		George F. Kramer, Ph.D., Senior Chemist

		RAB1/HED (7509P)

TO:		Susan Stanton/Daniel Rosenblatt, Risk Manager 05

		Registration Division (RD; 7505P)

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides.  The RD of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from the proposed (mint) and registered uses of the herbicide 4-(4-chloro-2-methylphenoxy)butanoic acid (MCPB).  The last risk assessment conducted by HED was for purposes of the Reregistration Eligibility Decision (RED) (E. Méndez, et al., 04-AUG-2005; DP#: 314047).

A summary of the findings and an assessment of human-health risk resulting from the proposed and registered uses of MCPB are provided in this document.  The risk assessment, residue chemistry review and dietary exposure assessment were provided by Sarah Levy (RAB1); the occupational/residential exposure assessment was provided by Mary Clock-Rust (RAB1); the hazard assessment was provided by Lisa Austin (RAB1); and the drinking water assessment was provided by James Lin of the Environmental Fate and Effects Division (EFED).

TABLE OF CONTENTS

  TOC \o "1-3" \u  1.0     Executive Summary	  PAGEREF _Toc210630471 \h  3

2.0	Ingredient Profile	  PAGEREF _Toc210630472 \h  7

2.1	Summary of Proposed Uses	  PAGEREF _Toc210630473 \h  7

2.2	Structure and Nomenclature	  PAGEREF _Toc210630474 \h  8

2.3	Physical and Chemical Properties	  PAGEREF _Toc210630475 \h  9

3.0	Hazard Characterization/Assessment	  PAGEREF _Toc210630476 \h  9

3.1	Summary of Toxicological Doses and Endpoints for Use in Human Risk Assessments	  PAGEREF _Toc210630477 \h  12

3.2	Dermal Absorption	  PAGEREF _Toc210630478 \h  13

3.3	Recommendation for Aggregate Exposure Risk Assessments	  PAGEREF _Toc210630479 \h  14

3.4	Classification of Carcinogenic Potential	  PAGEREF _Toc210630480 \h  14

3.5	Endocrine Disruption	  PAGEREF _Toc210630481 \h  14

4.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc210630482 \h  15

4.1   Comparative Metabolic Profile	  PAGEREF _Toc210630483 \h  15

4.2	Drinking Water Residue Profile	  PAGEREF _Toc210630484 \h  17

4.3	Food Residue Profile	  PAGEREF _Toc210630485 \h  17

4.4	International Residue Limits	  PAGEREF _Toc210630486 \h  19

4.5	Dietary Exposure Analyses	  PAGEREF _Toc210630487 \h  20

5.0	Residential (Non-Occupational) Exposure/Risk Pathway	  PAGEREF _Toc210630488 \h  21

6.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF _Toc210630489 \h  21

7.0	Cumulative Risk Characterization/Assessment	  PAGEREF _Toc210630490 \h  21

8.0	Occupational Exposure/Risk Pathway	  PAGEREF _Toc210630491 \h  22

8.1	Occupational Handler Exposure	  PAGEREF _Toc210630492 \h  22

8.1.1	Assumptions and Data Used in Assessment	  PAGEREF _Toc210630493 \h  22

8.1.2	Handler Risk Calculations	  PAGEREF _Toc210630494 \h  23

8.2	Occupational Post-application Exposure	  PAGEREF _Toc210630495 \h  25

9.0	Data Needs and Label Recommendations	  PAGEREF _Toc210630496 \h  26

9.1	Toxicology	  PAGEREF _Toc210630497 \h  26

9.2	Residue Chemistry	  PAGEREF _Toc210630498 \h  26

9.3	Occupational and Residential Exposure	  PAGEREF _Toc210630499 \h  27

1.0     Executive Summary

4-(4-chloro-2-methylphenoxy)butanoic acid (referred to as MCPB) is a chlorophenoxy herbicide currently registered to Nufarm Americas Inc., for the control or suppression of Canada thistle and certain other broadleaf weeds.  The only currently registered food/feed use of MCPB is on peas.  A tolerance for negligible residues of MCPB has been established under 40 CFR §180.318(a) for pea at 0.1 ppm (N) and is currently expressed in terms of MCPB per se.  There are currently no registered or proposed uses of MCPB that would result in residential exposure.

The Interregional Research Project No. 4 (IR-4), on behalf of the Agricultural Experiment Station of Washington in cooperation with Nufarm, has submitted a petition, PP#7E7257, proposing the establishment of a permanent tolerance for residues of the herbicide MCPB in/on:

Mint tops (leaves and stems)	0.25 ppm

Concurrently, the petitioner has   SEQ CHAPTER \h \r 1 requested an amendment of the end-use product, Thistrol® Herbicide (EPA Reg. No. 71368-5), a 2 lb acid equivalent (ae)/gal emulsifiable-concentrate (EC) formulation of MCPB sodium salt, to include a use pattern on mint.  Thistrol® is proposed for a fall application to established mint at up to 0.5 lb ae/A with a 40-day preharvest interval (PHI); a spring treatment is also proposed at an unspecified rate.

Hazard Assessment

MCPB has a low to moderate acute toxicity profile (Toxicity Category IV to II) via the oral, dermal and inhalation routes of exposure.  It is mildly to moderately irritating to the eye, but is not a dermal irritant or skin sensitizer.

The currently available toxicological database for MCPB is limited, thus it was supplemented with the closely related compound, 4-(chloro-2-methylphenoxy)acetic acid (MCPA).  Structurally, MCPB and MCPA only differ in that MCPB contains two additional carbon atoms.  In both animal and plant metabolism studies, the data indicate that MCPB is readily converted to MCPA.  It would not be unexpected that the toxicity profiles for these two compounds were similar at sub-lethal dose levels.  Therefore, HED concluded that the toxicity of these compounds were similar at sub-lethal dose levels.

Nephrotoxicity and hepatotoxicity appear to be the most prevalent hazard concerns for MCPB, based on the effects seen throughout the MCPA database and the limited toxicity data set available for MCPB.  Other toxic effects reported after MCPB or MCPA exposure included neurotoxicity (decreased arousal, impaired coordination and gait, reduced motor activity, reduced grip strength).  Developmental and reproduction toxicity studies conducted in MCPB and/or MCPA did not indicate an enhanced sensitivity or susceptibility to the young as developmental effects (delayed ossifications and decreased fetal or pup body weight) occurred at the same doses eliciting toxicity in the parental animals (mortality, decreased body weight, body weight gain and food consumption and increased absolute and relative ovary weights).  MCPB has been classified as a chemical “not likely to be carcinogenic to humans.”  Mutagenicity studies did not demonstrate evidence of mutagenic potential for MCPB.

Dose Response Assessment

Since the toxicity database for MCPB was limited, studies with the closely related compound, MCPA were used to select most toxicity endpoints.  The database for MCPA acid was used preferentially instead of MCPA-DMA (dimethyl amine salt) and MCPA-EHE (ethyl hexyl ester) because there are no DMA or EHE formulations with MCPB, as is the case with MCPA.

Although the dog is the most sensitive species to the effects of chlorophenoxy herbicides like MCPB, endpoint selection was based on the rodent studies.  Unlike rats and humans, dogs are uniquely sensitive to the toxic effects of this class of compounds due to their decreased ability to excrete organic acids.  Thus, the rat was considered to be a more suitable animal model for assessing the potential risks to the human population associated with MCPB exposure.

An acute neurotoxicity study in rats with MCPA was selected as the basis for an endpoint of concern for acute dietary risk assessment for the general population.  The endpoint was based on gait impairment in males.  An endpoint of concern attributable to a single dose for females 13-49 was not identified.  The endpoint for the chronic reference dose (cRfD) was selected from the chronic rat feeding study with MCPA.  This study reported clinical chemistry changes as well as gross and microscopic lesions of chronic progressive kidney disease.  This study was selected because the route and duration of exposure are appropriate for this risk assessment.  Incidental oral and inhalation (short and intermediate-term) endpoints are based on maternal mortality which occurred in a rabbit developmental study with MCPB.  No deaths occurred in the rabbit developmental study with MCPA.  Dermal (short and intermediate-term) endpoints are based on kidney toxicity (increased renal tubule mineralization) and decreased body weight gain in a 21-day dermal toxicity study with MCPA.  The endpoints for dermal and inhalation (long-term) were selected from the chronic rat feeding study with MCPA as noted above for the chronic dietary endpoint. The duration of exposure is appropriate for this risk assessment.  A dermal-absorption factor of 31% should be used (determined from MCPB dermal-absorption study) and HED assumes 100% oral equivalent for inhalation exposure.

Note that while the new 40 CFR revised Part 158 requirement for an immunotoxicity study has not yet been fulfilled, the existing data are sufficient for endpoint selection for exposure/risk assessment scenarios and for evaluation of the requirements under the Food Quality Protection Act (FQPA).  Further, the data requirements pertaining to immunotoxicity (see Section 9.1) should be fulfilled as a condition of registration.

FQPA Decision

There was no indication of quantitative or qualitative sensitivity noted in developmental rat studies with MCPB or MCPA.  In the developmental rat studies with MCPB and MCPA, decreased ossification and decreased fetal body weights occurred at the same dose causing decreased maternal body weight.  No toxicity to fetuses occurred in the MCPB and MCPA rabbit developmental studies.  A reproduction study was only available for MCPA; in this 1986 study, the only offspring toxicity was decreased weight gain while nursing which occurred at the same dose causing maternal toxicity (increased absolute and relative ovary weights).

A developmental neurotoxicity (DNT) study is required to be submitted because neurotoxicity was found in acute and subchronic neurotoxicity studies with MCPA in rats (decreased arousal, impaired coordination and gait, reduced motor activity, reduced grip strength), and similar signs of neurotoxicity can be expected with MCPB.  The neurotoxic effects seen in the acute neurotoxicity studies were the most sensitive acute effect identified and therefore were used in calculating the aRfD for MCPB.  Given these findings of neurotoxicity and sensitivity of the neurotoxic effects, EPA concluded that it lacks reliable data to remove the 10X FQPA Safety Factor (SF).

EPA began requiring functional immunotoxicity testing (series 870.7800) of all food and non-food use pesticides on December 26, 2007.  Since the requirement went into effect after this tolerance petition was submitted, these studies are not yet available for MCPB.  In the absence of specific immunotoxicity studies, EPA has evaluated the available toxicity data for MCPB and MCPA regarding potential immunotoxic effects.  Evidence of potential immunotoxicity was observed in subchronic 28-day oral toxicity studies in the mouse and dog with MCPA.  Involution of the spleen due to lymphocytic depletion was observed in both sexes at the highest-dose tested (HDT) and LOAEL of 453.7/223.9 mg/kg/day (Male/Female) in the mouse, and decreased thymus weights were seen in the dog at a dose of 30 mg/kg/day (HDT).  Lymphoid depletion was observed in the subchronic toxicity study in the dog at a dose of 44 mg/kg/day (HDT) of MCPB.  The NOAEL in the mouse and dog for potential immunotoxic effects was 173.4/69.2 mg/kg/day (M/F) and 20 mg/kg/day, respectively.  The NOAEL being used for calculation of the cRfD is 4.4 mg/kg/day.  The NOAEL from the mouse study (173.4/69.2 mg/kg/day (M/F)) provides the more appropriate reference for evaluating potential immunotoxic effects in humans.  Unlike rodents and humans, dogs are uniquely sensitive to the toxic effects of chlorophenoxy compounds such as MCPB due to their decreased ability to excrete organic acids and thus the effect levels in the mouse are more relevant to potential immunotoxicity in humans.

After weighing this evidence, EPA retains significant uncertainty regarding potential neurotoxic effects in infants and children but does not have such concerns for immunotoxicity.  The immunotoxic effects with most relevance to humans had a NOAEL over 10X greater than the NOAEL used in establishing the chronic RfD.  On the other hand, neurotoxic effects were the most sensitive acute effects seen in the database.  Additionally, the DNT study specifically addresses potential risks to developing animals.  Given these considerations, EPA concluded that it lacks reliable data to remove the 10X FQPA children’s SF.

Dietary Exposure and Risk

Acute and chronic dietary exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model - Food Consumption Intake Database (DEEM-FCID(, ver. 2.03).  DEEM-FCID( incorporates food consumption data from the United States Department of Agriculture (USDA) Continuing Surveys of Food Intakes by Individuals (CSFII; 1994-1996 and 1998).  A cancer dietary-exposure assessment was not conducted because MCPB was classified as “not likely to be carcinogenic to humans.”

The acute and chronic analyses assumed tolerance-level residues and 100% crop treated (CT) for all commodities.  Estimated drinking water concentrations (EDWCs; the EDWC values for mint were less than the values calculated for peas; therefore, the EDWC values for peas were used as the representative drinking water concentrations) were included in the current assessment as well.  For both acute and chronic dietary assessments, all population subgroups have risk estimates that do not exceed HED's levels of concern (LOCs).  For the acute assessment, the most highly exposed population subgroup is all infants (<1 year old; 5.4% of the aPAD).  For the chronic assessment, the most highly exposed population subgroup is also all infants (<1 year old; 22% of the cPAD).

Aggregate Risk

The proposed/registered MCPB uses are not expected to result in residential exposure.  Therefore, the acute and chronic exposure estimates provided in the Dietary Exposure Analyses (Section 4.5) represent acute and chronic aggregate exposure, respectively.  MCPA uses were not aggregated with the currently proposed/registered uses of MCPB as all MCPA residue levels were non-detectable in both the registered (peas) and proposed (mint) crops; and therefore, would not be a significant source of MCPA exposure.  If future uses of MCPB result in detectable residues of MCPA, then residues of MCPB and MCPA from all uses of both chemicals will be aggregated.

Occupational Exposure Estimates

MCPB is proposed for foliar use on mint to control field bindweed and other broadleaf weeds.  Thistrol® is a liquid formulation that contains 21.4% MCPB (2 lb ae per gallon) and is packaged in 2.5, 5, 50 and 220 (bulk) gallon containers.  A single seasonal application is expected to be made using groundboom and aerial sprayer equipment.  Based on the proposed use, exposure is possible for individuals that handle the end-use product, and for individuals that may enter treated mint growing areas to perform post-application activities (scouting).

Thistrol® labels require that applicators and other handlers wear long-sleeved shirt and long pants, waterproof gloves and shoes plus socks.

An occupational risk assessment has been conducted for handlers/applicators exposures as well as for post-application exposures.  A single application is expected per season; however, handler margins of exposure (MOEs) represent short- and intermediate-term exposures since the doses and endpoints are the same and were identified from the same study (21-day dermal toxicity study in rabbits).  Handlers’ dermal and inhalation risks do not exceed HED's LOC (MOEs > 100) if mixer/loaders wear baseline personal-protective equipment (PPE; long pants and long-sleeved shirt) and gloves as required by Thistrol® labels.  Respirators are not required.  Workers may be dermally exposed to MCPB upon entering previously treated areas to perform specific work activities (i.e., irrigation, scouting, etc.).  All MOEs for post-application dermal exposure exceed the target MOE of 100 on Day 0 indicating that the post-application risks do not exceed HED's LOC.

MCPB technical material has been classified in Toxicity Category II for acute dermal toxicity and acute eye irritation.  MCPB is classified in Acute Toxicity Category IV for primary skin irritation.  Per the Worker Protection Standard (WPS), a 24-hr restricted-entry interval (REI) is required for chemicals classified under Acute Dermal Toxicity Category II.  The proposed Thistrol® label indicates an REI of 12 hrs.  HED recommends the labels be amended to comply with the WPS (requiring a 24-hr REI).

  SEQ CHAPTER \h \r 1 Regulatory Recommendations

Pending submission of a revised Section B and a revised Section F, there are no toxicology, residue chemistry, or occupational/residential issues that would preclude granting a conditional registration for the requested use of the MCPB herbicide on mint.  Unconditional registration may be appropriate upon resolution of the deficiencies cited in Section 9.0.  The proposed use and the submitted data support the following permanent tolerances for the combined residues of free and conjugated MCPB and MCPA as follows:

Peppermint, tops	0.20 ppm

Spearmint, tops	0.20 ppm

Note to RD:  The current tolerance established under 40 CFR §180.318 is for residues of 4-(2-methyl-4-chlorophenoxy)butyric acid) [MCPB] per se in/on peas at 0.1 ppm.  The tolerance expression should be revised in accordance with recommendations from the HED Metabolism Committee decision (08-JUN-1995) and the HED Chapter of the RED (Memo, E. Méndez, 04-AUG-2005; DP#: 314047)).  The residues of concern for both tolerance enforcement and risk assessment purposes are MCPB and MCPA, free and conjugated.  The preferred chemical names for MCPB and MCPA are 4-(4-chloro-2-methylphenoxy)butanoic acid and (4-chloro-2-methylphenoxy)acetic acid, respectively.

Peppermint, tops	0.20 ppm

Spearmint, tops	0.20 ppm

2.0	Ingredient Profile

MCPB is a selective, chlorophenoxy herbicide used postemergence as a broadcast foliar application to control broad-leaved annual and perennial weeds (i.e., Canada thistle).  The end-use products are sodium salts and are available as liquid formulations.  The only currently registered food/feed use of MCPB is on peas.  A tolerance for negligible residues of MCPB has been established under 40 CFR §180.318(a) for pea at 0.1 ppm (N) and is currently expressed in terms of MCPB per se.

2.1	Summary of Proposed Uses

The petitioner has submitted an undated draft label for the 2 lb ae/gal EC formulation (Thistrol® Herbicide; EPA Reg. No. 71368-5) of MCPB sodium salt.  Thistrol® is a liquid formulation and is packaged in 2.5, 5, 50 and 220 (bulk) gallon containers.  The proposed Section 3 use directions for mint are presented in Table 2.1.

Table 2.1.  Summary of Directions for Use of MCPB.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate

(lb ae/A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb ae/A)	PHI

(days)

Mint

Early Postemergence;

Ground or aerial	2 lb ae/gal EC

[71368-5]	0.25-0.5	Not specified

(NS)	NS	40

	Use Directions and Limitations:  For control of winter annual weeds, a fall application at 0.25-0.5 lb ae/A may be applied.  A single spring application works best for field bindweed suppression.  Application may be made alone or as a tank mix with other herbicides.  Do not use this product if minor mint injury is unacceptable.  Plant-back intervals (PBIs) for rotational crops are not specified.  Long-sleeved shirt, long pants, waterproof gloves, and shoes plus socks are required for applicators and other handlers.  REI = 12 hours.

Conclusions.  The proposed use directions are incomplete to allow evaluation of the residue data relative to the proposed use on mint.  A revised Section B should be submitted to specify a maximum seasonal rate for mint.  The submitted crop field trial data will support a maximum total application rate of 1.8 lb ae/A, with a single fall application at up to 1 lb ae/A and a subsequent spring application at up to 0.8 lb ae/A.  In addition, the label should be revised to specify minimum ground and aerial spray volumes.  The need for plant-back intervals (PBIs) will be determined following the review of an acceptable MCPB confined rotational crop study; however, until that time, a revised Section B should be submitted to specify that rotation can only occur to a MCPB or MCPA registered crop.

Structure and Nomenclature

  TC \l2 "2.2	Structure and Nomenclature

  SEQ CHAPTER \h \r 1 Table 2.2.  MCPB Nomenclature.

Chemical structure

Common name	MCPB

IUPAC name	4-(4-chloro-o-tolyloxy)butyric acid

CAS name	4-(4-chloro-2-methylphenoxy)butanoic acid

CAS registry number	94-81-5

End-use product (EP)	2 lb ae/gal EC sodium salt formulation (Thistrol® Herbicide; EPA Reg. No. 71368-5)

Chemical structure of

MCPA metabolite

(4-chloro-2-methylphenoxy)acetic acid

2.3	Physical and Chemical Properties

  TC \l2 "2.3	Physical and Chemical Properties

Table 2.3.  Physicochemical Properties of MCPB.

Parameter	Value

Melting range	101.5-103.0ºC

pH	5.6 (1% w/v)

Density	1.26 g/mL at 20ºC

Water solubility at 20ºC	60.4 mg/L (purified water)

29.9 mg/L in pH 4 buffer

3.83 mg/L in pH 7 buffer

>250 g/L in pH 10 buffer

Solvent solubility at 20ºC	n-heptane			0.414 g/L

xylene			37.6 g/L

methylene chloride		69.9 g/L

n-octanol			71.6 g/L

ethyl acetate		144 g/L

methanol & acetone	>250 g/L

Vapor pressure 	4 x 10-7 torr at 25ºC

Dissociation constant, pKa	4.6 at 20ºC

Octanol/water partition coefficient, Log(KOW)	pH 4	3.45

pH 7	1.33

pH 10	-0.21

UV/visible absorption spectrum						dm/

solvent 		conc.	max	  A       (mol/cm)

water/MeOH	20.78	229	0.881	9700

		103.9	280	0.797	1750

			286sh	0.697	1530

Acid/MeOH	20.78	229	0.888	9770

		103.9	280	0.799	1760

			287sh	0.697	1530

Base/MeOH	20.78	229	0.871	9590

		103.9	280	0.800	1760

			287sh	0.695	1530

Reference:  RD Memorandum; H. Podall, 08-MAR-2002; DP# 279212.

.

3.0	Hazard Characterization/Assessment

A summary of the hazard characterization and dose-response assessment was taken from the MCPB RED (E. Méndez, et al., 04-AUG-2005; DP#: 314047) and is provided below.  For more details about the hazard and dose response assessment, please see the RED or the HIARC Report (TXR#: 0052196).  The MCPB risk assessment team re-evaluated the endpoints selected previously.

Hazard Assessment

The toxicity database for MCPB was limited and was supplemented with the closely related compound, MCPA.  MCPB differs from MCPA only in having an organic acid that is two carbons longer than on MCPA.  Toxicity was very similar between MCPB and MCPA at doses below a lethal dose.  This is not unexpected as MCPB is metabolized to MCPA as evidenced in both plant and animal metabolism studies.

Subchronic studies available for both MCPB and MCPA. MCPB caused liver toxicity, kidney toxicity, and hematological effects in rats and dogs; and small testes, prostate, and thymus in the dog study.  These effects are seen with other chlorophenoxy herbicides, and at similar doses in the subchronic studies with MCPA.  Neurotoxicity was not seen in the MCPB subchronic studies but was noted in MCPA neurotoxicity studies (decreased arousal, impaired coordination and gait, reduced motor activity, reduced grip strength).  A dermal toxicity study was available only for MCPA; this study found microscopic evidence of kidney injury.

Developmental studies were available for both MCPB and MCPA.  In the developmental rat study with MCPB, decreased ossification and decreased fetal body weights occurred at the same dose causing decreased maternal body weight.  Similar effects occurred at similar doses in the developmental rat study with MCPA.  No toxicity to fetuses occurred in the MCPB and MCPA rabbit developmental studies; maternal mortality occurred in the study with MCPB but not with MCPA.  A reproduction study was only available for MCPA; in this 1986 study, the only offspring toxicity was decreased weight gain while nursing which occurred at the same dose causing maternal toxicity (increased absolute and relative ovary weights).

Chronic studies were only available for MCPA.  Liver and kidney toxicity occurred in chronic rat and dog studies with MCPA, but at lower doses than in the subchronic studies.  There was no increase in the number of tumors in the rat or mouse carcinogenicity studies with MCPA.  MCPB was negative in a battery of mutagenicity assays except for a positive result in a chromosomal aberrations assay in the Chinese-hamster ovary (CHO) cells.  Similar results were found for mutagenicity testing with MCPA.  The cancer classification for MCPA was "not likely to be carcinogenic to humans."

Although the dog is the most sensitive species to the effects of chlorophenoxy herbicides like MCPB, endpoint selection was based on the rodent studies.  Unlike rats and humans, dogs are uniquely sensitive to the toxic effects of this class of compounds due to their decreased ability to excrete organic acids.  Thus, the rat was considered to be a more suitable animal model for assessing the potential risks to the human population associated with MCPB exposure.

Dose Response Assessment

Since the toxicity database for MCPB was limited, studies with the closely related compound, MCPA, were used to select most toxicity endpoints.  The database for MCPA acid was used preferentially instead of MCPA-DMA and MCPA-EHE because there are no DMA or EHE formulations with MCPB, as is the case with MCPA.

Although the dog is the most sensitive species to the effects of chlorophenoxy herbicides like MCPB, endpoint selection was based on the rodent studies.  Unlike rats and humans, dogs are uniquely sensitive to the toxic effects of this class of compounds due to their decreased ability to excrete organic acids.  Thus, the rat was considered to be a more suitable animal model for assessing the potential risks to the human population associated with MCPB exposure.

Note that while the new Part 158 requirement for an immunotoxicity study has not yet been fulfilled, the existing data are sufficient for endpoint selection for exposure/risk assessment scenarios and for evaluation of the requirements under the FQPA.  Further, the data requirements pertaining to immunotoxicity (see Section 9.1) should be fulfilled as a condition of registration.

FQPA Decision

There was no indication of quantitative or qualitative sensitivity noted in developmental rat studies with MCPB or MCPA. In the developmental rat studies with MCPB and MCPA, decreased ossification and decreased fetal body weights occurred at the same dose causing decreased maternal body weight.  No toxicity to fetuses occurred in the MCPB and MCPA rabbit developmental studies.  A reproduction study was only available for MCPA; in this 1986 study, the only offspring toxicity was decreased weight gain while nursing which occurred at the same dose causing maternal toxicity (increased absolute and relative ovary weights).

A DNT study is required to be submitted because neurotoxicity was found in acute and subchronic neurotoxicity studies with MCPA in rats (decreased arousal, impaired coordination and gait, reduced motor activity, reduced grip strength), and similar signs of neurotoxicity can be expected with MCPB.  The neurotoxic effects seen in the acute neurotoxicity studies were the most sensitive acute effect identified and therefore were used in calculating the aRfD for MCPB.  Given these findings of neurotoxicity and sensitivity of the neurotoxic effects, EPA concluded that it lacks reliable data to remove the 10X FQPA SF.

EPA began requiring functional immunotoxicity testing (series 870.7800) of all food and non-food use pesticides on December 26, 2007.  Since the requirement went into effect after this tolerance petition was submitted, these studies are not yet available for MCPB.  In the absence of specific immunotoxicity studies, EPA has evaluated the available toxicity data for MCPB and MCPA regarding potential immunotoxic effects.  Evidence of potential immunotoxicity was observed in subchronic 28-day oral toxicity studies in the mouse and dog with MCPA.  Involution of the spleen due to lymphocytic depletion was observed in both sexes at the HDT and LOAEL of 453.7/223.9 mg/kg/day (Male/Female) in the mouse, and decreased thymus weights were seen in the dog at a dose of 30 mg/kg/day (HDT).  Lymphoid depletion was observed in the subchronic toxicity study in the dog at a dose of 44 mg/kg/day (HDT) of MCPB.  The NOAEL in the mouse and dog for potential immunotoxic effects was 173.4/69.2 mg/kg/day (M/F) and 20 mg/kg/day, respectively.  The NOAEL being used for calculation of the cRfD is 4.4 mg/kg/day.  The NOAEL from the mouse study (173.4/69.2 mg/kg/day (M/F)) provides the more appropriate reference for evaluating potential immunotoxic effects in humans.  Unlike rodents and humans, dogs are uniquely sensitive to the toxic effects of chlorophenoxy compounds such as MCPB due to their decreased ability to excrete organic acids and thus the effect levels in the mouse are more relevant to potential immunotoxicity in humans.

After weighing this evidence, EPA retains significant uncertainty regarding potential neurotoxic effects in infants and children but does not have such concerns for immunotoxicity.  The immunotoxic effects with most relevance to humans had a NOAEL over 10X greater than the NOAEL used in establishing the chronic RfD.  On the other hand, neurotoxic effects were the most sensitive acute effects seen in the database.  Additionally, the DNT study specifically addresses potential risks to developing animals.  Given these considerations, EPA concluded that it lacks reliable data to remove the 10X FQPA children’s SF.

In estimating MOEs, the level of concern (LOC) is for MOEs <100 for the dermal and inhalation risk assessments.  A 31% dermal-absorption factor and a 100% inhalation-absorption factor were used.  The acute toxicity of MCPB technical is shown in Table 3.0 below.

Table 3.0.  Acute Toxicity of MCPB Technical.

Guideline No.	Study Type	MRID	Results	Toxicity Category

870.1100	Acute oral [rat]	00116340	LD50=1570 MG/KG	III

870.1100	Acute oral [rat]	00144801	LD50=4300 mg/kg	III

870.1200	Acute dermal [rabbit]	00116342	LD50 > 10000 mg/kg	IV

870.1200	Acute dermal [rat]	00144799	LD50 > 2000 mg/kg	II

870.1300	Acute inhalation [rat]	41630001	LC50 > 1.14 mg/L	III

870.2400	Acute eye irritation [rabbit]	00116343	Moderately irritating	II

870.2400	Acute eye irritation [rabbit]	00144797 	Mildly irritating	III

870.2500	Acute dermal irritation [rabbit]	00144798 	Non-irritating	IV

870.2600	Skin sensitization [Guinea Pig]	00144800 	Negative	IV

3.1	Summary of Toxicological Doses and Endpoints for Use in Human Risk Assessments

Endpoints and doses selected for MCPB risk assessment are shown below in Tables 3.1.1 and 3.1.2.

Table 3.1.1.  Summary of Toxicological Doses and Endpoints for MCPB for Use in Dietary Human Risk Assessments.

Exposure

Scenario

Point of Departure

Uncertainty/

FQPA Safety Factors

RfD, PAD, Level of Concern for Risk Assessment

Study and Toxicological Effects

Acute Dietary (general population including females 13-49 years old) NOAEL = 200 mg/kg/day	UFA = 10x

UFH = 10x

UFDB = 10x

FQPA SF = 10x	Acute RfD = 0.2 mg/kg/day

aPAD = 0.2 mg/kg/day	Acute neurotoxicity (MCPA, rat).  LOAEL = 400 mg/kg/day based on gait impairment in males.

Chronic Dietary (all populations)

NOAEL = 4.4 mg/kg/day

 	UFA = 10x

UFH = 10x

UFDB = 10x

FQPA SF = 10x	Chronic RfD = 0.0044 mg/kg/day

cPAD = 0.0044 mg/kg/day	Chronic toxicity (MCPA, rat).  LOAEL = 17.6 mg/kg/day based on liver and kidney toxicity.

Cancer (oral)

Classification:  Not Likely to be carcinogenic to humans.

Point of Departure (PoD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no-observed adverse-effect level.  LOAEL = lowest-observed adverse-effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  UFDB= incomplete database.  FQPA SF = FQPA Safety Factor.  PAD = population-adjusted dose (a = acute, c = chronic).  RfD = reference dose.

Table 3.1.2.  Summary of Toxicological Doses and Endpoints for MCPB for Use in Occupational Human Risk Assessments.

Exposure

Scenario

Point of Departure

Uncertainty/

FQPA Safety Factors

RfD, PAD, Level of Concern for Risk Assessment

Study and Toxicological Effects

Dermal Short-

(1-30 days) and Intermediate-

(1-6 months) Term	NOAEL = 25 mg/kg/day

  SEQ CHAPTER \h \r 1 	UFA = 10x

UFH = 10x

Occupational LOC for MOE = 100

	21-Day dermal toxicity (MCPA, rabbit).  NOAEL = 100 mg/kg/day, LOAEL = 1000 mg/kg/day based on kidney toxicity and decreased body weight gain.  Dermal absorption of MCPB is 4x that of MCPA.

Dermal Long-Term

(>6 months)	NOAEL = 4.4 mg/kg/day	UFA = 10x

UFH = 10x

Dermal- absorption factor = 31%

Occupational LOC for MOE = 100

	Chronic toxicity (MCPA, rat).  LOAEL = 17.6 mg/kg/day based on liver and kidney toxicity.

Inhalation Short- (1-30 days) and Intermediate- (1-6 months) Term	NOAEL = 5 mg/kg/day	UFA = 10x

UFH = 10x

Inhalation-absorption rate = 100%

Occupational LOC for MOE = 100	Developmental toxicity (MCPB, rabbit).  LOAEL = 20 mg/kg/day based on maternal mortality.

Inhalation Long-Term (>6 months)	NOAEL = 4.4 mg/kg/day	UFA = 10x

UFH = 10x

Inhalation-absorption rate = 100%	Occupational LOC for MOE = 100	Chronic toxicity (MCPA, rat).  LOAEL = 17.6 mg/kg/day based on liver and kidney toxicity.

Cancer (oral)	Classification:  Not Likely to be carcinogenic to humans.

Point of Departure (PoD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no-observed adverse-effect level.  LOAEL = lowest-observed adverse-effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  UFDB= incomplete database.  MOE = margin of exposure.  LOC = level of concern.

3.2	Dermal Absorption

The dermal absorption factor for MCPB is 31% compared to a dermal absorption factor of 7% for MCPA.  Because a dermal toxicity study with MCPB is not available, the point of departure (PoD) for short- and intermediate-term dermal exposure is based on the dermal toxicity study with MCPA.  The MCPA dermal toxicity study has a NOAEL of 100 mg/kg/day and a LOAEL of 1000 mg/kg/day based on kidney toxicity and decreased body weight gain.  However, the dermal absorption of MCPB is 4x that of MCPA, and because of this a dermal toxicity study conducted with MCPB would have a lower NOAEL than that with MCPA.  Therefore, the dermal NOAEL from the MCPA study was divided by 4 to obtain a PoD of 25 mg/kg/day for MCPB.  (See Appendix for calculations)

Although the dermal absorption value could have been applied to an oral endpoint, it was preferred to use the route specific data rather than extrapolating to the oral route of exposure in which toxicity and metabolism may vary somewhat from the dermal route.

3.3	Recommendation for Aggregate Exposure Risk Assessments

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (i.e., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

No residential uses are proposed or registered for MCPB.  Moreover, MCPB has been classified as “not likely to be carcinogenic to humans.”  Consequently, only acute and chronic dietary exposure risk assessments (i.e., food + water) should be aggregated.  MCPA uses were not aggregated with the currently proposed/registered uses of MCPB as all MCPA residue levels were non-detectable in these crops (peas and mint); and therefore, would not be a significant source of MCPA exposure.  If future uses of MCPB result in detectable residues of MCPA, then residues of MCPB and MCPA from all uses of both chemicals will be aggregated.  The acute and chronic exposure estimates provided in Section 4.5 of this document represent acute and chronic aggregate exposure, respectively.

3.4	Classification of Carcinogenic Potential

The carcinogenic potential of MCPB was classified as “not likely to be carcinogenic to humans” based on the absence of increased numbers of tumors in the rat and mouse carcinogenicity studies and the lack of mutagenicity.  Similar results were found for mutagenicity testing with MCPA.  The cancer classification for MCPA is "not likely to be carcinogenic to humans."

3.5	Endocrine Disruption tc  \l 0 "0023.6	Endocrine disruption"

EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) “may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.”  Following recommendations of its Endocrine Disruptor and Testing Advisory Committee (EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system.  EPA also adopted EDSTAC’s recommendation that the Program include evaluations of potential effects in wildlife.  For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations.  As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program (EDSP).

When additional appropriate screening and/or testing protocols being considered under the Agency’s EDSP have been developed, MCPB may be subjected to further screening and/or testing to better characterize effects related to endocrine disruption.

4.0	Dietary Exposure/Risk Characterization  TC \l1 "5.0	Dietary Exposure/Risk Characterization

The assessment of the residue chemistry data submitted in support of the proposed petition was completed on 30-SEP-2008 (Memo, S. Levy; DP#: 349646).  The drinking water assessment was completed by EFED on 27-FEB-2008 (Memo, J. Lin, DP#: 343745).  The dietary exposure assessment was completed by HED on 30-SEP-2008 (Memo, S. Levy; DP#: 350511).

4.1   Comparative Metabolic Profile tc \l2 "3.1 	Comparative Metabolic Profile

β-oxidation.  This results in MCPB being converted to MCPA.  MCPB was also shown to be converted to MCPA in plant metabolism studies.

Nature of the Residue in Plants/Livestock

HED Memo:  S. Funk, 20-JUN-1995; DP#s: 196282 and 207498

For purposes of this petition, based on the pea foliage metabolism data and since mint is a minor crop (low-consumption commodity), the nature of the residue in primary crops is adequately understood based on a metabolism study conducted on peas.  MCPB is metabolized to MCPA, and the latter is hydroxylated to 6-chloro-2-hydroxymethylphenoxy acetic acid.  The HED Metabolism Committee (08-JUN-1995) determined that the residues to be regulated for both tolerance and risk assessment purposes in plant commodities are the free and conjugated MCPB and MCPA.  There are no livestock feedstuffs associated with the proposed use on mint.  Therefore, data requirements for livestock metabolism are not relevant to this tolerance petition.

NOTE to RD:  The current tolerance established under 40 CFR §180.318 is for residues of 4-(2-methyl-4-chlorophenoxy)butyric acid) [MCPB] per se in/on peas at 0.1 ppm.  The tolerance expression should be revised in accordance with recommendations from the HED Metabolism Committee decision (08-JUN-1995) and the HED Chapter of the RED (Memo, E. Méndez, 04-AUG-2005; DP#: 314047)).  The residues of concern for both tolerance enforcement and risk assessment purposes are MCPB and MCPA, free and conjugated.  The preferred chemical names for MCPB and MCPA are 4-(4-chloro-2-methylphenoxy)butanoic acid and (4-chloro-2-methylphenoxy)acetic acid, respectively.

Confined and Field Accumulation in Rotational Crops

HED Memo:  F. Fort, 09-MAR-2004; DP#: 197125

HED Memo:  F. Fort, 30-JUL-2007; DP#: 340491

HED Memo:  F. Fort, 12-MAR-2008; DP#: 305068

Previously, the MCPB Task Force had submitted a request for a waiver of the requirements for a confined accumulation in rotational crops study for MCPB, based on the fact that MCPB has a very short half-life and that MCPB soil residues would have gone through a minimum of 5 half-lives prior to planting another crop (3-4 months for peas).  Residues of MCPA, a degradation product of MCPB, would be more likely to be present then residues of MCPB.  The MCPB Task Force suggested that EPA, therefore, rely on the MCPA rotational crop study.

The Agency agreed that MCPA would more likely be found in soil and that this requirement may be satisfied with a confined accumulation in rotational crops study with MCPA since this compound is the major metabolite for MCPB.  However, the study that the registrant referred to was found to be deficient (Memo, F. Fort, 09-MAR-2004; DP#: 197125).  In their waiver request, the MCPB Task Force stated that EPA’s primary reason for not accepting the previous study (MRID 40961301) was that a maximum rate of 0.75 lb ae/A was used, whereas labels included rates of up to 10.75 lb ae/A.  The MCPB Task Force stated that all the labels have either  been changed or are in the process of being changed so that no more than 0.75 lb ae/A will be registered.  Thus, EPA’s objection will no longer apply.  HED concluded that if the registrant decreases the maximum use rate for MCPA to no more than 0.75 lb ae/A, then granting the waiver request is appropriate (Memo, F. Fort, 12-MAR-2008; DP#: 305068).

The submitted MCPB mint crop field trial data support a maximum total application rate of 1.8 lb ae/A, with a single fall application at up to 1 lb ae/A and a subsequent spring application at up to 0.8 lb ae/A.  Because this application rate is significantly higher than the conditions HED recommended for previously (Memo, F. Fort, 12-MAR-2008; DP#: 305068) when granting the MCPA confined rotational crop data waiver, HED recommends that the MCPB Task Force submit a MCPB confined rotational crop study.  HED further recommends that the confined rotational crop study monitor for both MCPB and MCPA.

The need for field rotational crop studies and/or rotational crop restrictions will be determined following the review of the outstanding MCPB confined rotational crop study.  Until an acceptable study is submitted, rotation should be limited to crops from which MCPA and MCPB use is registered.

The residues of concern in plants, livestock, and drinking water are shown in Table 4.1 below.

Table 4.1.  Residues of Concern in Crops, Livestock, and Drinking Water.

Matrix	Tolerance Expression	Residues for Risk Assessment

Pea and mint	free and conjugated MCPB and MCPA	free and conjugated MCPB and MCPA

Livestock	NA for purposes of this petition 	NA for purposes of this petition

Drinking Water	NA	MCPB and MCPA

4.2	Drinking Water Residue Profile

The drinking water residues used in the dietary risk assessments were provided by EFED in a memorandum by J. Lin (27-FEB-2008; DP#: 343745) and incorporated directly into this dietary assessment.  Water residues were incorporated in the DEEM-FCID into the food categories “water, direct, all sources” and “water, indirect, all sources.”  The EDWC values for mint were less than the values calculated for peas; therefore, the EDWC values for peas were used as the representative drinking water concentrations (Memo, K. Costello, 03-AUG-2005; DP#: 314053).  Both monitoring analysis and modeling approach were applied in the pea assessment.  A summary of the model estimates for drinking water from both surface water and groundwater sources is shown below.  Surface water estimates were used in the acute and chronic food and water dietary exposure assessments.  For purposes of this assessment, the highest (i.e., most conservative) values were used for the acute (54.7 ppb) and chronic (13.5 ppb) assessments.  The models and their descriptions are available at the EPA internet site: http://www.epa.gov/oppefed1/ models/water/.

Table 4.2.  Summary of Surface Water and Groundwater EDWCs for MCPB based on Peas; Annual Application Rate:  1.5 lb. ae/A.

	Surface Water EDWC (ppb)1	Groundwater EDWC (ppb)2

Acute	54.7	2.1

Chronic (non-cancer)	13.5	2.1

1  From the FQPA Index Reservoir Screening Tool (FIRST) model.

2  From the Screening Concentration in Ground Water (SCI-GROW) model.

4.3	Food Residue Profile

Residue Analytical Methods

The Agency previously requested that a method for the determination of free and conjugated MCPB and MCPA be developed for enforcement purposes.  A gas chromatography/mass spectrometry (GC/MS) analytical method entitled, “An Analytical Method for the Determination of Residues of MCPB and its Metabolite MCPA in Peas, Vines and Pods” was previously submitted for plant commodities.  Upon review, the Agency found the method inadequate and requested the method be revised and new method validation data be submitted for the revised method.  After acceptable method validation of the revised method, an independent laboratory validation (ILV) should also be conducted.

Analytical method and validation data were submitted for MCPB, MCPA and 2-HMCPA in pea matrices.  These data have been reviewed by HED and are classified as scientifically acceptable (Memo, T. Goodlow, in preparation, DP#: 330176).  HED noted that confirmatory raw data should be submitted in order to verify the recoveries reported in the analytical method and ILV studies.  The review of the method and validation were sent to the Biological and Economic Analysis Division’s (BEAD’s) Analytical Chemistry Laboratory (ACL) and deemed adequate for enforcement purposes (e-mail, C. Stafford to D. Vogel, 16-JUN-2008).

For data collection, samples of mint tops (leaves and stems) and oil were analyzed for residues of free and conjugated MCPB and MCPA using a GC/MS method similar to that developed for peas.  The lowest level of method validation (LLMV) for MCPB and MCPA was 0.05 ppm each in/on mint tops and oil.  The method was adequately validated prior to and in conjunction with the analysis of field trial samples.

Multiresidue Method (MRM)

No MRM testing data were submitted with this petition.  The FDA PESTDATA database (dated JUN-2005) indicates that MCPB is completely recovered using multiresidue method Section 402 E1 and Section 402 E2, but a small recovery (4-13%) using multiresidue method Section 402.  Recovery of MCPA is variable (60-131%) using multiresidue method Section 402 (method for acids and phenols).  The database did not include any information for any of the other test methods.  Use of MRMs for purposes of MCPB tolerance enforcement is not adequate, as there is no hydrolysis step to release conjugated residues.

Magnitude of Residues in Plants

Crop field trial data have been submitted on mint tops.    SEQ CHAPTER \h \r 1 The results from these studies are discussed below and summarized in Table 4.3.1.

Table 4.3.1.  Summary of Residue Data from Mint Field Trials with MCPB.

Commodity	Total Applic. Rate

(lb ae/A)	PHI (days)	Analyte	Residue Levels (ppm)1

n	Min.	Max.	HAFT2	Median	Mean	Std.

Dev.

Proposed use pattern = Fall and spring applications may be made with fall treatment at 0.25-0.5 lb ae/A.  Spring application and total application rates not specified.  The proposed PHI is 40 days.

Mint tops	1.71-1.81	38-40	MCPB	10	<0.05	0.13	0.12	0.08	0.08	0.03

	MCPA	10	<0.05	<0.05	<0.05	0.05	0.05	--

	Total3	10	<0.10	<0.18	<0.17	0.13	0.13	0.03

1  The LLMV (0.05 ppm) was used for any results reported as <LLMV.

2  HAFT = Highest-Average Field Trial.

3  Total combined MCPB and MCPA residues.

The submitted residue data for mint tops are adequate.  The number and locations of crop field trials are in accordance with OPPTS Guideline 860.1500, and the appropriate samples were collected at the proposed PHI, following a fall application made at up to 2x the maximum proposed application rate and subsequent spring application made at up to 1.5x the maximum proposed application rate.  A residue decline trial was not conducted, but none is requested because of the dormant and early season applications, and long PHI.

The residue data for mint tops were entered into the Agency’s tolerance spreadsheet as specified by the Guidance for Setting Pesticide Tolerances Based on Field Trial Data standard operation procedure (SOP) to determine appropriate tolerance levels.  The recommended tolerance level was adjusted by 1.5x, because of the exaggerated application rate.  Therefore, the recommended tolerance level for MCPB (including MCPA) in/on peppermint, tops and spearmint, tops is 0.20 ppm (based on 0.18 ppm = 0.27 ppm/1.5).

The proposed tolerance should be revised to reflect the recommended tolerance level and correct commodity definitions as specified in Table 4.3.2.  A revised Section F should be submitted.

Table 4.3.2.   Tolerance Summary for MCPB.

Commodity	Proposed Tolerance (ppm)	Recommended Tolerance (ppm)	Comments;

Correct Commodity Definition

Mint tops (leaves and stems)	0.251	0.202	Separate tolerances should be established for Peppermint, tops and Spearmint, tops

1   The petitioner indicated that the proposed tolerance is based on the maximum residue limit (MRL) Calculator.  In those cases where no detectable residues were found (LLMV = 0.05 ppm), a value of 0.025 ppm was used by the petitioner to calculate the MRL.

2   HED notes that the recommended tolerance level is based on the MRL Calculator.  In those cases where no quantifiable residues were found (total combined MCPB and MCPA LLMV = 0.10 ppm), maximum likelihood estimation (MLE) procedures were needed to impute censored values.  Furthermore, the recommended tolerance level was divided by 1.5x, because of the exaggerated application rate.  The unrounded tolerance value and the appropriate rounding rule was applied to the revised tolerance calculation.  Therefore, the recommended tolerance level for MCPB (including MCPA) in/on peppermint, tops and spearmint, tops is 0.20 ppm (based on 0.18 ppm = 0.27 ppm/1.5).

Magnitude of Residues in Livestock

There are no livestock feedstuffs associated with the proposed use on mint.  Therefore, data requirements pertaining to meat, milk, poultry, and eggs are not relevant to this tolerance petition.

Storage Stability

Residues of MCPB and MCPA were determined to be stable in/on mint tops and oil stored frozen for up to 3.6 and 3 months, respectively.  These data support the frozen storage conditions and durations of samples from the submitted mint field trial and processing studies.

Processed Food/Feed

An adequate processing study was conducted on mint.  The study showed that the combined residues of MCPB and MCPA did not concentrate in mint oil; therefore, a tolerance for mint oil is not required.

Confined/Field Accumulation in Rotational Crops

HED recommends that the MCPB Task Force submit a MCPB confined rotational crop study.  HED recommends further that the confined rotational crop study monitor for both MCPB and MCPA.

The need for field rotational crop studies and/or rotational crop restrictions will be determined following the review of the outstanding MCPB confined rotational crop study.  Until an acceptable study is submitted, rotation should be limited to crops from which MCPA and MCPB use is registered.

4.4	International Residue Limits TC \l3 "5.1.11	International Residue Limits

  SEQ CHAPTER \h \r 1 There are no established or proposed Codex, Canadian, or Mexican maximum residue limits (MRLs) for MCPB.

4.5	Dietary Exposure Analyses TC \l2 "5.2  Dietary Exposure and Risk

The dietary exposure assessment was completed by HED in a review dated 30-SEP-2008 (Memo, S. Levy; DP#: 350511) and the drinking water exposure assessment was completed by EFED in a review dated 27-FEB-2008 (Memo, J. Lin; DP#: 343745).

Acute and chronic dietary (food and drinking water) exposure and risk assessments were conducted for MCPB using the DEEM-FCID™, Version 2.03 which uses food consumption data from the U.S. Department of Agriculture’s CSFII from 1994-1996 and 1998.  A cancer dietary-exposure assessment was not conducted because MCPB was classified as “not likely to be carcinogenic to humans.”

The acute and chronic dietary assessments are updates of the previous dietary assessment conducted in 2005 (Memo, F. Fort, 04-AUG-2005; DP#: 314047).  The proposed raw agricultural commodities (RACs) associated with this action were added at the HED-recommended tolerance levels to the last dietary assessment to estimate dietary exposure.  The acute and chronic analyses also incorporated the acute and chronic surface drinking water estimates resulting from application of MCPB to peas.  The EDWC values for mint were lower than the values calculated for peas; therefore, the EDWC values for peas were used as the representative drinking water concentrations.  The acute and chronic dietary assessments are unrefined, Tier 1 assessments, assuming 100% CT for all commodities and tolerance-level residues.

For both acute and chronic dietary assessments, all population subgroups have risk estimates that do not exceed HED's LOCs.  For the acute assessment, the most highly exposed population subgroup is all infants (<1 year old; 5.4% of the aPAD).  For the chronic assessment, the most highly exposed population subgroup is also all infants (<1 year old; 22% of the cPAD).  The use of anticipated residues (ARs), empirical processing factors, and/or %CT would further refine HED’s exposure and risk estimates; however, refinement is not needed at this time.  The estimated exposures/risks from food and water are summarized in Table 4.5.2 for all populations.

Table 4.5.  Summary of Dietary (Food + Drinking Water) Exposure and Risk for MCPB.

Population Subgroup	Acute Dietary1

(95th Percentile)	Chronic Dietary1

	Dietary Exposure (mg/kg/day)	%aPAD*	Dietary Exposure (mg/kg/day)	% cPAD*

U.S. Population (total)	0.002870	1.4	0.000294	6.7

All Infants (< 1 year old)	0.010731   	5.4	0.000977	22

Children 1-2 years old	0.004527   	2.3	0.000455	10

Children 3-5 years old	0.004120   	2.1	0.000415	9.4

Children 6-12 years old	0.002865  	1.4	0.000284	6.5

Youth 13-19 years old	0.002334 	1.2	0.000211	4.8

Adults 20-49 years old	0.002653   	1.3	0.000273	6.2

Adults 50+ years old	0.002408 	1.2	0.000289	6.6

Females 13-49 years old	0.002664 	1.3	0.000271	6.2

1 Acute dietary endpoint of 0.2 mg/kg/day applies to the general U.S. population and all population subgroups.  Chronic dietary endpoint of 0.0044 mg/kg/day applies to the general U.S. population and all population subgroups.

*  The highest %aPAD and %cPAD are bolded.

5.0	Residential (Non-Occupational) Exposure/Risk Pathway  TC \l1 "6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no registered or proposed residential uses for MCPB.  Spray drift is always a potential source of exposure to residents nearby to spraying operations.  This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from groundboom application methods.  The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices.  The Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling.  The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT® computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift and risks associated with aerial as well as other application types where appropriate.

6.0	Aggregate Risk Assessments and Risk Characterization

In accordance with the FQPA, when there are potential residential exposures to a pesticide, aggregate risk assessment must consider exposures from three major routes: oral, dermal, and inhalation.  There are three sources for these types of exposures:  food, drinking water, and residential uses.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (i.e., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

The proposed/registered MCPB uses are not expected to result in residential exposure.  Therefore, the acute and chronic exposure estimates provided in the Dietary Exposure Analyses (Section 4.5) represent acute and chronic aggregate exposure, respectively, and therefore, do not exceed HED's LOCs.  MCPA uses were not aggregated with the currently proposed/registered uses of MCPB as all MCPA residue levels were non-detectable in both the registered (peas) and proposed (mint) crops; and therefore, would not be a significant source of MCPA exposure.  If future uses of MCPB result in detectable residues of MCPA, then residues of MCPB and MCPA from all uses of both chemicals will be aggregated.

7.0	Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to MCPB and any other substance and MCPB does not appear to produce a toxic metabolite produced by other substances.  For the purposes of this tolerance action, therefore, EPA has assumed that MCPB does not have a common mechanism of toxicity with other substances.  For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at   HYPERLINK http://www.epa.gov/pesticides/cumulative/. http://www.epa.gov/pesticides/cumulative/.

8.0	Occupational Exposure/Risk Pathway  TC \l1 "9.0	Occupational Exposure/Risk Pathway

The occupational exposure and risk assessment was performed by HED (Memo, M. Clock-Rust; DP#: 349647).  The proposed use is on mint, and occupational exposure is possible for individuals that handle the end-use product, Thistrol®, and/or for individuals that may enter treated mint growing areas.  Therefore, occupational handler and post-application exposure was assessed.

8.1	Occupational Handler Exposure

It is expected that mint will be treated with MCPB by groundboom tractor sprayer or by fixed-wing aircraft.  Since chemical-specific handler exposure data were not available, unit exposures (mg ai/lb ai handled) for handlers were obtained from the Pesticide Handler Exposure Database (PHED, Version 1.1).

8.1.1	Assumptions and Data Used in Assessment

Chemical-specific data for assessing exposure during pesticide handling activities were not submitted to the Agency in support of this Section 3 application for MCPB on mint.  It is HED policy to use data from PHED to assess handler exposures for regulatory actions when chemical-specific data are not available (HED Exposure Science Advisory Council (ExpoSAC), SOP Number .007, JAN-1999).

The assumptions, parameters and factors used in the risk and exposure calculations include:

Application Rate:  The application rate is the maximum rate identified on the proposed Thistrol® label.  The maximum application rate for treatment of mint using groundboom or aerial equipment is 0.5 lb ae (acid equivalents)/acre.

Unit Exposures (UE):  The PHED UE for mixer/loaders and applicators is expressed in mg per pound of ai handled (mg/lb ai).

Amount Treated:  Daily area treated values are based on the area that can be reasonably applied in a single day for each exposure scenario, based on the application method and formulation/packaging type (standard HED values).

Body Weight (BW):  The average body weight of an adult male (70 kg) was used for both dermal and inhalation risk assessment.

MOE:  Margin of exposure.  A measure of the level of risk; estimated by comparing a benchmark dose to exposure.

Equations/Calculations:  The following equations were used to calculate handler exposure and risk:

Exposure (mg/kg/day) = Rate (lb ae/acre) x UE (mg /lb ai) x Area Treated (acres/day) / BW (kg)

Where:

Rate =	Maximum application rate on product label (lb ai/acre).

UE (Unit Exposure) = Exposure value derived from August 1998 PHED Surrogate Exposure Table (mg/lb ai)

Area Treated = Maximum area treated per day (acres/day).

BW = Body weight (70 kg).

100% Absorption was assumed for both dermal and inhalation risk assessment.

Dermal or Inhalation MOE (Dermal and Inhalation Risk) = NOAEL (mg/kg/day) / Exposure (mg/kg/day)

As a single application is expected per season, handler MOEs represent short- and intermediate-term exposures since the doses and endpoints are the same and were identified from the same study (21-day dermal toxicity study in rabbits).  Calculations of handlers’ dermal and inhalation risks do not exceed HED's LOC (MOEs >100) if mixer/loaders wear baseline PPE (long pants and long-sleeved shirt) and gloves as required by Thistrol® labels.  Respirators are not required.  Workers may be dermally exposed to MCPB upon entering previously treated areas to perform specific work activities (i.e., irrigation, scouting, etc.).  All MOEs for post-application dermal exposure exceed the target MOE of 100 on Day 0 indicating that the post-application risks do not exceed HED's LOC.

As explained above (Hazard Characterization Section of this document), dermal and inhalation risks were calculated separately.  Short- and intermediate-term dermal risk was estimated using the NOAEL from a dermal toxicity study (NOAEL = 25 mg/kg/day; kidney toxicity and decreased body weight gain) while short- and intermediate-term inhalation risk was estimated using the NOAEL from an oral toxicity study (NOAEL = 5 mg/kg/day; maternal mortality).

8.1.2	Handler Risk Calculations

The mixer/loader dermal and inhalation exposure scenarios resulting from foliar treatment of mint are presented below.  The MOEs for dermal and inhalation risk do not exceed HED’s LOCs as long as handlers wear gloves, as required on the label.  See Table 8.1.2 below for exposure and risk.Table 8.1.2.  Summary of Exposure and Risk for Occupational Handlers of MCPB.

Exposure Scenario

(Scenario #)	Dermal Unit Exposure (mg/lb ai)1	Inhalation

Unit

Exposure

(mg/lb ai)1	Use Site	Application

Rate

(lb ai/A)2	Area Treated

(A/day)3	Daily Dose

(mg/kg/day)4	Short-/Int-term

MOE5

Dermal	Inhalation	Dermal	Inhalation

Mixer/Loader

Mixing/Loading Liquids for Groundboom Application	2.9

(no gloves)

or

0.023

(w/gloves)	0.0012

(no respirator)

	Mint	0.5	80	0.013 (w/gloves)

	0.0007	1900 (w/gloves)	7300

Mixing/Loading Liquids Aerial Application

	350

0.058 (w/gloves)

	0.003	430 (w/gloves)	1700

Applicator

Applying Sprays with Open cab Groundboom	0.014	0.00074	Mint	0.5	80	0.008 (w/gloves

or no gloves)	0.00042	3100 (w/gloves or no gloves)	12,000

Applying Sprays with Fixed-wing Aircraft 	0.005

(no gloves)	0.000068	Mint	0.5	350	0.013

(no gloves)	0.00017	150,000

(no gloves)	29,000

1. Dermal unit exposure values represent long pants, long-sleeved shirts, shoes, and socks; values representing the addition of chemical-resistant gloves are shown for those scenarios in which the MOEs do not reach 100 at baseline.  Inhalation unit exposure values represent no respirator. Values are reported in the PHED Surrogate Exposure Guide dated August 1998.

2. Application rates are based on maximum value on the proposed Thistrol® label.

3. Daily area treated is based on the area that can be reasonably applied in a single day for each exposure scenario, based on the application method and formulation/packaging type (standard HED values).

4. Daily Dose (mg/kg/day) = (Unit Exposure * % Absorption * Application rate * Area treated) / Body Weight of 70 kg.

5. Short-/Intermediate-Term MOE = NOAEL/Daily Dose.  The dermal NOAEL is 100 mg/kg/day, and the inhalation NOAEL is 5 mg/kg/day.  The LOC is 100.

8.2	Occupational Post-application Exposure

The proposed use of MCPB involves foliar applications to mint.  Therefore, post-application exposure is possible for workers entering treated mint fields.  No chemical-specific dislodgeable- foliar residue (DFR) data have been submitted for this use.  Therefore, HED used default assumptions regarding the expected amount of contact workers entering treated fields may experience.

Transfer coefficients (TCs) are used to relate the foliage residue values to activity patterns (i.e., scouting) to estimate potential human exposure.  The TCs used in this assessment are from an interim TC policy developed by HED’s Science Advisory Council for Exposure using proprietary data from the Agricultural Re-entry Task Force (ARTF) database (Policy # 3.1).  For mint, the TC used is 1500 cm2/hr for scouting activities in mature foliage plants.  Because chemical-specific dissipation data were not submitted, it is HED policy to assume that 20% of the application rate is available to dislodge on the day of treatment.

HED used the following equations to calculate post-application exposure and risk:

DFR (ug/cm2) = AR x CF1 (4.54E+8 ug/lb) x CF2 (2.47E-8 A/cm2) x 0.2

Where:

DFR: the amount of MCPB available for transfer to skin from the leaf surface.

AR: Application rate (0.5 lb ai/acre).

CF: conversion factors (ug to lbs and acres to cm2).

20% of the amount applied (0.2) is available for transfer.

Daily Dose (mg/kg/day) = [DFR x  TC x  ET x  / CF x BW]

Where:

TC: Transfer coefficient (cm2/hr).

ET: Exposure time (8 hrs/day).

CF: Conversion factor (1000 ug/mg).

BW: Body weight (70 kg).

The estimated short-/intermediate-term MOEs are presented below.  Due to the use of standard assumptions for TCs and amount of residue available for transfer, HED considers this a conservative assessment of post-application risk.  The results of the post-application exposure and risk assessment indicate that a MOE of 100 is achieved on Day 0, and therefore do not exceed HED’s LOC.

Table 8.2.  Exposure and Risk for Occupational Post-Application Activities in Mint.

Crop Group	Application Rate

(lb ai/A)	DFR

(ug/cm2)1	Transfer

Coefficient

(cm2/hr)2	Post-application Day (t)	Short-Term

	Daily Dose3

(mg/kg/day)	Dermal MOE4

Mint	0.5	1.1	1,500	0	0.19	130

1 DFR (ug/cm2) = Application rate (0.5 lb ai/A) x CF (4.54E+8 ug/lb) x CF (2.47E-8 A/cm2) x 0.2.

2 Transfer Coefficient: 1,500 (cm2/hr) -scouting in mature/medium foliaged plants.

3 Daily Dose = (DFR x TC x 8-hr Exposure Time) / (CF: 1000 ug/mg) x 70-kg BW.

4 MOE = NOAEL/Daily Dose.  Dermal Short- and Intermediate-term NOAEL = 25 mg/kg/day.

REI

MCPB technical material has been classified in Toxicity Category II for acute dermal toxicity and acute eye irritation.  MCPB is classified in Acute Toxicity Category IV for primary skin irritation.  Per the WPS, a 24-hr REI is required for chemicals classified under Acute Dermal Toxicity Category II.  The proposed Thistrol® label indicates an REI of 12 hrs.  HED recommends the labels be amended to comply with the WPS (requiring a 24-hr REI).

9.0	Data Needs and Label Recommendations  TC \l1 "10.0	Data Needs and Label Recommendations

Toxicology

*   DNT study.

*   28-day Inhalation Study in Rats (abbreviated 90-day protocol).  This study is required because there is the potential for repeated occupational exposure via this route.

*   Immunotoxicity Study.  An immunotoxicity study is now a data requirement in the 40 CFR revised Part 158.

Residue Chemistry

*   Revised Section B.  The petitioner should submit a revised Section B to specify a maximum seasonal use rate for mint.  The submitted crop field trial data will support a maximum total application rate of 1.8 lb ae/A, with a single fall application at up to 1 lb ae/A and a subsequent spring application at up to 0.8 lb ae/A.  In addition, the label should be revised to specify minimum ground and aerial spray volumes.  Appropriate PBIs will be determined following the review of an acceptable MCPB confined rotational crop study; however, until that time, a revised Section B should be submitted to specify that rotation should be limited to crops from which MCPB or MCPA use is registered.

*   Revised Section F.  The petitioner should submit a revised Section F to reflect the residues of concern and to reflect correct commodity definition and tolerance levels as reflected in Table 4.3b.

*   Analytical Enforcement Method.  Confirmatory raw data should be submitted in order to verify the recoveries reported in the analytical method and ILV studies.

*   Confined Accumulation in Rotational Crops.  A satisfactory confined accumulation in rotational crops study following application of MCPB is requested before the appropriate PBIs and the need for a limited field rotational crop study can be determined.  HED recommends further that the confined rotational crop study monitor for both MCPB and MCPA.

Occupational and Residential Exposure

*   Revised Section B.   HED recommends the labels be amended to comply with the WPS (requiring a 24-hr REI).

  SEQ CHAPTER \h \r 1 Attachments

Attachment 1:  MCPB Chemical Structures.

Attachment 2:  Toxicity Profile for MCPB.

Attachment 3:  Toxicity Profile for MCPA.

Attachment 4:  Comparison of MCPB and MCPA Dermal Absorption.

RDI: D.Vogel (01-OCT-2008); Branch (07-MAY-2008), RAB1 Chemists (26-MAR-2008)

S. Levy: S-10953: PY1:<PHONE_NUMBER>: 7509P: RAB1

Petition#: 7E7257

DP#: 343743

PC Code: 019201

Attachment 1:  MCPB Chemical Structures.

Common name;

Company code	Chemical name	Chemical structure

MCPB	4-(4-chloro-2-methylphenoxy)butanoic acid

MCPA	(4-chloro-2-methylphenoxy)acetic acid

Attachment 2:  Toxicity Profile for MCPB.

Guideline No./Study Type

MRID No. (year)/Classification/ Doses

Results

870.3100

90-Day oral toxicity (rat)

42883602 (1993)

Acceptable/guideline

0,  100,  500,  2500 ppm

(0,  6,  32,  158  mg/kg/day)

NOAEL =  158 mg/kg/day

LOAEL > 158 mg/kg/day

870.3150

90-Day oral toxicity (dog)

42883603 (1993)

Acceptable/guideline

0,  12,  80,  800,  1800 ppm

(0,  0.4,  2,  25,  44 mg/kg/day

NOAEL =  2 mg/kg/day

LOAEL = 25 mg/kg/day based on small prostate and clinical chemistry (elevated BUN)

870.3200

21-Day dermal toxicity (rabbit)

116346 (1970)

Supplementary.

NOAEL/LOAEL could not be determined.

870.3465  Inhalation  toxicity

N/A

N/A

870.3700a

Prenatal Developmental (rat)

 40865402 (1988)

Acceptable/guideline

0,  25,  100,  225  mg/kg/day

Maternal NOAEL =  25 mg/kg/day

LOAEL =  100 mg/kg/day based on ( BW gain

Developmental NOAEL = 25 mg/kg/day

LOAEL = 100 mg/kg/day based on ( fetal BW and ( ossification

870.3700b

Prenatal Developmental  (rabbit)

 40865401 (1988)

Acceptable/guideline

0,  1,  5,  20  mg/kg/day

Maternal NOAEL = 5 mg/kg/day

LOAEL = 20 mg/kg/day based on mortality

Developmental NOAEL = 20 mg/kg/day

LOAEL > 20 mg/kg/day, HDT

870.3800  Reproduction

N/A

N/A

870.4100  Chronic toxicity

 N/A

N/A

870.4200  Carcinogenicity

N/A

N/A

870.5100

Gene Mutation: Ames assay

Gene Mutation:  HGPRT

   40564302 (1988)

Acceptable/guideline

   40564303 (1988)

Acceptable/guideline

No increase in mutant colonies.

No increase in mutant colonies.

870.5375 Cytogenetics: Chromosomal Aberrations in CHO Cells

40564301 (1988)

Acceptable/guideline

Evidence of chromosomal aberrations at cytotoxic concentration with S9.

870.5550 Other Genotoxic Effects:  UDS

 40564304 (1987)

Acceptable/guideline

No evidence of unscheduled DNA synthesis.

870.6200a Acute Neurotoxicity Study

N/A

N/A

870.6200b Subchronic Neurotoxicity

N/A

N/A

870.6300  D.T.

N/A

N/A

870.7485

Metabolism

 44818101 (1998)

Acceptable/guideline

Oral:  5 mg/kg and 100 mg/kg

MCPB was well absorbed (~90%), urine was major route of excretion (~87%), most excreted by 48 hr with no bioaccumulation.  MCPA was major metabolite (~36%).

870.7600 In Vivo Dermal Penetration (rat)

46732601 (2003)

Acceptable/guideline

0.067 and 4.00 mg/cm2 skin

Dermal absorption is 31.3%.

Attachment 3:  Toxicity Profile for MCPA.

Guideline No./Study Type	MRID No. (year)/Classification/ Doses	Results

28-day toxicity study (mouse)	00165470 (1985)

Acceptable/Non-guideline

0, 100, 300, 900, 2700 ppm

Males: 0, 19.1-22.0, 56.3-67.7, 173.4-184.8, or 453.7-820.1 mg/kg/day

Females: 0, 20.7-26.2, 69.2-73.9, 193.4-223.9, 442.3- 956.3 mg/kg/day

	NOAEL male 173.4- 184.8 / females: 69.2-73.9.

LOAEL = males: 453.7-820.1/female: 193.4-223.9 based on cloudy swelling in the liver in females, and clinical signs consistent with general motor disturbances, body weight loss, decreased adrenal weight, cachexia, hepatotoxicity (increased liver weight, increase in clinical chemistry parameters, and histologic observations of cloudy swelling and necrobiosis/necrosis), involution of the spleen due to lymphocytic depletion, and testicular atrophy in males.

28-day range finding (dog)	00061368 (1978)

Acceptable/Non-guideline

0, 8, 20, or 30 mg/kg/day	NOAEL was not established.

LOAEL = 8 mg/kg/day based on changes in clinical chemistry (increased ALT activity and BUN).

90-day oral toxicity (rat)	00165471 (1985)

Acceptable/Guideline

0, 50, 150, or 450 ppm

Males: 0, 3.6, 10.9, or 32.6 mg/kg/day

Females: 0, 4.0, 12.1, or 35.8 mg/kg/day

	NOAEL =10.9 mg/kg/day.

LOAEL = 32.6 mg/kg/day based on increased absolute and relative kidney weights, increased clotting time, increased creatinine levels, and presence of crystalluria (oxalate, calcium phosphate, and urate).

90-day oral toxicity (dog)	00106595 (1980)

Acceptable/Guideline

0, 7.5, 25.0, 77-86, 300-342, or 1198- 1370 ppm

(0, 0.3, 1.0, 3.0, 12.0, 48.0 mg/kg/day).

	NOAEL = 1 mg/kg/day.

LOAEL = 3 mg/kg/day based on renal toxicity as evidenced by increased phenol red dye retention (males only).

870.3200

21/28-Day dermal toxicity (rabbit)	42715001 (1992)

Guideline

10, 100, 1000 mg/kg/day.

	Systemic NOAEL =100 mg/kg/day.

Systemic LOAEL=1000 mg/kg/day based on kidney findings (increase in incidence of mineralization in renal tubule) and the decrease in body weight gain.

Dermal NOAEL = 10 mg/kg/day.

Dermal LOAEL = 100 mg/kg/day based on erythema, desquamation, and diffuse acanthosis.

870.3700a

Prenatal developmental (rat)	42723801 (1994)

Acceptable/Guideline

15, 60, and 120 mg/kg/day	Maternal NOAEL = 60 mg/kg/day

LOAEL = 120 mg/kg/day based on decreases in body weight gain and food consumption during treatment.

Developmental NOAEL=60 mg/kg/day.

LOAEL = 120 mg/kg/day based on decreased placental and fetal body weights and an increase in the number of fetuses with skeletal retardation.

870.3700b

Prenatal developmental (rabbit)	42723802 (1993)

Acceptable/Guideline

15, 30, and 60 mg/kg/day	Maternal NOAEL = 30 mg/kg/day.

LOAEL = 60 mg/kg/day based on decreases in body weight and food consumption during the treatment period.

Developmental NOAEL = 200 mg/kg/day.

LOAEL = was not established.

870.3800

Reproduction and fertility effects (rat)	40041701

(1986)

Acceptable/Guideline

0, 2.5, 7.5, and 22.5

 mg/kg/day

	Parental Systemic NOAEL =7.5 mg/kg/day.

Parental Systemic LOAEL = 22.5 mg/kg/day based on increased absolute and relative ovary wts.

Reproduction NOAEL = M/F 22.5 mg/kg/day.

Reproduction

LOAEL was not established.

Offspring NOAEL= 7.5 mg/kg/day.

Offspring LOAEL=22.5 mg/kg/day based on decreased pup weight gain during lactation.

870.4300b

Chronic Toxicity (dog)	00164352 (1986)

Acceptable/Guideline

Males: 0, 0.2, 1.02, or 5.32 mg/kg/day

Females: 0, 0.21, 1.02 or 5.12 mg/kg/day.

	Systemic NOAEL =0.2 mg/kg/day.

LOAEL= 1.02 mg/kg/d based on hepatotoxicity (increased SGPT, SGOT, triglycerides and cholesterol levels with histopathology changes) and nephrotoxicity [increased urea nitrogen, potassium, and creatinine levels with histopathology changes (increased pigmentation of the proximal tubular epithelium) in kidneys].

870.4300

Chronic/Carcinogenicity (rat)	40634101 (1986)

Acceptable/Guideline

0, 20, 80, or 320 ppm

Males: 0, 1.1, 4.4, or 17.6 mg/kg/day

Females: 1.4, 5.7, or 23 mg/kg/day.

	NOAEL =4.4 mg/kg/day

LOAEL = 17.6 mg/kg/day based on hepatotoxicity (increased SGPT levels in females) and nephrotoxicity (increased urea nitrogen in females).  In addition, there was an increase in the retraction and granular surface of the kidney associated with an increase in the chronic progressive nephropathy in the males.

Not carcinogenic

870.4300

Chronic/Carcinogenicity (mouse)	40792301 (1986)

Acceptable/Guideline

0, 20, 100, or 500 ppm

Males: 0, 3.2, 15.7, or 79.5 Females: 0, 3.9, 19.5, or 97.2 mg/kg/day NOAEL = M/F:  15.7/3.9 mg/kg/day.

LOAEL =M/F: 79.5/19.5 mg/kg/day based on decreased females: renal hyperplasia

males: histopathology changes in kidneys.

Not carcinogenic

870.5100

Gene Mutation-In vitro Bacterial Gene Mutation 	42840403 (1993)

Acceptable

0, 50, 150, 500, 1500 and 5000 ug/plate	Not mutagenic

870.5385

Cytogenetics -In Vivo Mammalian Cytogenetics - Chromosomal aberration assay in Chinese hamster bone marrow 	40027501 (1993)

Acceptable/Guideline

  SEQ CHAPTER \h \r 1 0, 33, 200 and 1200 mg/kg/bw	Not mutagenic

870.5915

Cytogenetics-other

In Vivo Mammalian Cytogenetics - Sister Chromatid Exchange assay in Chinese hamsters	00148720 (1985)

Acceptable/Guideline

  SEQ CHAPTER \h \r 1 0, 1200 mg/kg/bw 	Weakly mutagenic

870.6200

Acute Neurotoxicity (rat)

	43562602 (1994)

Acceptable/Guideline

single doses

M: 0, 200, 400, or 800 mg/kg

F: 0, 150, 300, or 600 mg/kg 	NOAEL = M/F: 200/150 mg/kg/day.

LOAEL = M/F: 400/300 mg/kg/day based on gait impairment in male rats only.

870.6200

Subchronic Neurotoxicity (rat)

	43562601 (1994)

Acceptable/Guideline

0, 50, 500, and 2500 ppm

M: 0, 3, 34, or 177 mg/kg/day

F: 0, 4, 42, or 188 mg/kg/day	NOAEL = M/F: 34/42 mg/kg/day.

LOAEL = M/F: 177/188 mg/kg/day based on decreased body weight and body weight gains, liver pathology, changes in clinical chemistry (ALT, AST, ALP) and hematological parameters.

In addition, testicular atrophy, reduced values of forelimb grip strength (day 50 only) and  reduced values in the foot splay test (day 22 only) in males and reduced values of hindlimb grip strength in females.

870.7485

Metabolism and pharmacokinetics (rat)	00041634 (1978)

Unacceptable/Guideline

Single dose of 100 mg/kg or

daily dose of 1 mg/kg for 14 days.	Total recovery of dosed radioactivity = 93-101%. (8 days)

86-95% (urine), 6% (feces), 0% (expired air), 2-6% in bile.  Major component in the urine was MCPA, 55-79%.

870.7485

Metabolism and pharmacokinetics (rat)	43755202 (1995)

Acceptable/Guideline

single dose of 5 or 100 mg/kg, or a single dose of 5 mg/kg.	Readily absorbed.  Low dose and High dose t ½ elimination (hr)–plasma Male 19 and 11; Female 34 and 21; Plasma tmax (hrs) Male 2.7 and 2.4; Female 2.4 and 4.2.  AUC Males 210 and 5180; Females 250 and 5628.  Total recovery of dosed radioactivity = 96.1-110.1% (4 days), 74-86% (urine), 10-25% (cage washing), 2-5% (feces), (2.3% (tissues and carcasses); not detectable (expired air).  Metabolite profile in urine was similar between sexes and among dose groups. Major component in the urine was MCPA   (53-69%), HMCPA ( 7-13%): 4-chloro-2-hydroxymethyl-phenoxyacetic acid.  Primary pathway = Excretion of unchanged MCPA and Oxidation to HMCPA and excretion.  Minor pathway = Glycine conjugation of MCPA -detected but not quantified.

870.7485

Metabolism and pharmacokinetics

(dog)

	45595301 (1999) and 45595302 (2000)

Acceptable/Non-guideline

Dosed phenyl-U-14C)-MCPA via gelatin capsule at a single oral dose of 5 or 100 mg/kg.	MCPA is rapidly absorbed.  Plasma tmax (hours) ~4.5 for the low dose (males only) 7 for the high dose (males only); t ½ elimination (hr)–plasma 45 for the low dose (males only); 47 for the high dose (males only); AUC                            2539  for the low dose (males only) and 20454  for the high  dose (males only).  Overall % of dose recovered = 79-85%. --The low overall recovery of radioactivity could be explained by prolonged renal clearance which was still occurring at the 120-hour termination point.

low dose and high dose -urine (% of dose) 58% and 34%;  feces (% of dose) 17% and 49%  4 Major components in the urine were MCPA 14.5% and 2.6%; HMCPA 4.2% and 6.7%; Metabolite 1 (a taurine conjugate)                    8.6% and 9.7%; Metabolite 2 (a glycine conjugate) 28.1% and 5.9%.  3 Major components in the feces MCPA 7.5% and 19%; Metabolite 1 (tentatively a taurine conjugate) 3.1% and 8.9%; Metabolite 2 (tentatively a glycine conjugate) 0.9% and 2.4%.

Attachment 4:  Comparison of MCPB and MCPA Dermal Absorption.

Because a dermal toxicity study with MCPB was not available for the previous MCPB risk assessment, an endpoint from a dermal toxicity study with MCPA was used to assess dermal exposure and risk to MCPB.  Since the last MCPB risk assessment was written, a dermal exposure study with MCPB has been completed which allows comparison of dermal absorption of MCPB and MCPA.

Previous risk assessments recommended a value of 7% dermal absorption for MCPA, even though a higher dose of MCPA resulted in an increased dermal absorption value of 22%.  The value of 7% dermal absorption with MCPA was recommended because this value resulted from a dermal exposure of 0.09 mg/cm2 which is more relevant to worker exposure than the much higher 7.0 mg/cm2 which resulted in 22% dermal absorption.

It is unusual for higher doses to result in increased absorption because ordinarily higher doses result in a saturation of absorption and a decreased percentage dermal absorption.  The increased absorption with increasing dose for MCPA and MCPB is attributed to damage to the barrier layer of the skin by the acidic herbicide.

To calculate dermal exposure, compound remaining on the skin was not included in the dermal absorption calculations.  Although compound remaining on the skin is sometimes considered available for absorption, this was not the case with both MCPB and MCPA in which continued absorption after 10 hours did not occur.

Both the MCPB and MCPA dermal absorption studies used similar application methods, reported radioactivity in the same matrices, and used similar doses.  As shown in the table below, it can be concluded that a dermal absorption value of 31% is appropriate for use with MCPB and that MCPB is absorbed to a 4x greater extent than is MCPA.

MCPB vs MCPA Dermal Absorption at 10 Hours.

Matrix	MCPB

4.0 mg/cm2	MCPA

7.0 mg/cm2	MCPB

0.067 mg/cm2	MCPA

0.09 mg/cm2

Urine	24.83 ± 4.35	8.95	18.58 ± 5.36	4.79

Feces	0.74 ± 0.44	0.08	0.58 ± 0.37	0.01

Cage wash	1.37 ± 0.52	0.74	1.34 ± 0.33	0.25

Blood cells	1.14 ± 0.32	0.54	0.29 ± 0.10	0.08

Plasma	0.71 ± 0.38	0.59	0.58 ± 0.12	0.13

Carcass	52.77 ± 10.19	11.2	9.93 ± 2.05	1.83

ABSORBED	81.56%	22.09%	31.3%	7.09%

Surrounding skin	1.51 ± 0.77	6.43	0.98 ± 0.64	0.68

Skin site	2.62 ± 0.81	5.68	18.69 ± 9.97	11.44

Protective cover	2.48 ± 0.76	6.73	3.56 ± 3.00	0.63

Skin wash	16.19 ± 4.84	53.49	36.19 ± 7.88	71.31

RECOVERY	104.36	94.42	90.72	91.15

MCPB:MCPA ratio at high dose:  3.7           MCPB:MCPA ratio at low dose:  4.4

Page   PAGE  12  of   NUMPAGES  36

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0 of   NUMPAGES  36

Page   PAGE  25  of   NUMPAGES  36


PAPERWORK REDUCTION ACT SUBMISSION PAPERWORK REDUCTION ACT SUBMISSION Please read the instructions before completing this form. For additional forms or assistance in completing this form, contact your agency's Paperwork Clearance Officer. Send two copies of this form, the collection instrument to be reviewed, the Supporting Statement and any additional documentation to: Office of Information and Regulatory Affairs, Office of Management and Budget, Docket Library, Room 10102, 725 17th Street NW Washington, DC 20503.

1. Agency/ Subagency originating request U. S. EPA, OECA, Manufacturing, Energy, and Transportation Div 2. OMB control number b. None a 2060  0026 __ __ __ __

3. Type of information collection ( check one)

a. New collection b. Revision of a currently approved collection c. X Extension of a currently approved collection d. Reinstatement, without change, of a previously approved collection for which approval has expired e. Reinstatement, with change, of a previously approved collection for which approval has expired f. Existing collection in use without an OMB control number 4. Type of review requested ( check one)

a. X Regular b. Emergency  Approval requested by: / /

c. Delegated 5. Small entities Will this information collection have a significant economic impact on a substantial number of small entities? Yes X No For b f, note item A2 of Supporting Statement Instructions 6. Requested expiration date a. X Three years from approval date b. Other Specify: / /___

7. Title NSPS Subpart D , Standards of Performance for Fossil Fuel Fired Steam Generating Units 8. Agency form number( s) ( If applicable)

EPA ICR No. 1052.06 file:/// C|/ MyStuff/ 1052om06. htm ( 1 of 6) [ 7/ 10/ 03 1: 04: 16 PM] PAPERWORK REDUCTION ACT SUBMISSION 9. Keywords steam generating units; information collection; standards of performance 10. Abstract Owners or operators of affected facilities must: make one time only notifications of occurrences such as construction/ reconstruction and startup; submit reports containing information such as monitoring system performance and excess emissions; and maintain records of occurrences such as startups and shutdowns. Responses to this information collection are deemed to be mandatory, per Section 114( a) of the Clean Air Act.

11. Affected public ( Mark primary with " P" and all others that apply with " X")

a. Individuals or households d. Farms b. P Business or other for profit e. Federal Government c. Not for profit institutions f. State, Local or Tribal Government 12. Obligation to respond ( Mark primary with " P" and all others that apply with " X")

a. Voluntary b. Required to obtain or retain benefits c. P Mandatory 13. Annual reporting and recordkeeping hour burden a. Number of respondents 660 b. Total annual responses 2640 1. Percentage of these responses collected electronically 0 %

c. Total annual hours requested 62,865 d. Current OMB inventory 62,865 e. Difference 0 f. Explanation of difference 1. Program Change 2. Adjustment 14. Annual reporting and recordkeeping cost burden ( in thousands of dollars)

a. Total annualized capital/ startup costs 0 b. Total annual costs ( O& M) 9,900 c. Total annualized cost requested 9,900 d. Current OMB inventory 26 e. Difference 9,874 f. Explanation of difference 1. Program change 2. Adjustment 9,874 file:/// C|/ MyStuff/ 1052om06. htm ( 2 of 6) [ 7/ 10/ 03 1: 04: 16 PM] PAPERWORK REDUCTION ACT SUBMISSION 15. Purpose of information collection ( Mark Primary With " P" and all hers that apply with " X")

a. __ Application for benefits e. __ Program planning or management b. __ Program evaluation f. __ Research c. __ General purpose statistics g. _ P_ Regulatory or compliance d. __ Audit 16. Frequency of recordkeeping or reporting ( check all that apply)

a. X Recordkeeping b. Third party disclosure c. X Reporting 1. On occasion 2. Weekly 3. Monthly 4. X Quarterly 5. Semi annually 6. Annually 7. Biannually 8. Other ( describe)

17. Statistical methods Does this information collection employ statistical methods?

Yes X No 18. Agency contact ( person who can best answer questions regarding the content of this submission)

Name: Jordan Spooner Phone: 202 564 7058 19. Certification for Paperwork Reduction Act Submissions On behalf of this Federal agency, 1 certify that the collection of information encompassed by this request complies with'

5 CFR 1320.9.

NOTE: The text of 5 CFR 1320.9, and the related provisions of 5 CFR 1320.8( b)( 3), appear at the end of the instructions. The certification is to be made with reference to those regulatory provisions as set forth in the instructions.

The following is a summary of the topics, regarding the proposed collection of information, that the certification covers:

file:/// C|/ MyStuff/ 1052om06. htm ( 3 of 6) [ 7/ 10/ 03 1: 04: 16 PM] PAPERWORK REDUCTION ACT SUBMISSION ( a) It is necessary for the proper performance of agency functions;

( b) It avoids unnecessary duplication;

© It reduces burden on small entities;

( d) It uses plain, coherent, and unambiguous terminology that is understandable to respondents;

( e) Its implementation will be consistent and compatible with current reporting and recordkeeping practices;

( f) It indicates the retention periods for recordkeeping requirements;

( g) It informs respondents of the information called for under 5 CFR 1320.8( b)( 3):

( I) Why the information is being collected;

( ii) Use of information;

( iii) Burden estimate;

( iv) Nature of response ( voluntary, required for a benefit, or mandatory);

( v) Nature and extent of confidentiality; and ( vi) Need to display currently valid OMB control number;

file:/// C|/ MyStuff/ 1052om06. htm ( 4 of 6) [ 7/ 10/ 03 1: 04: 16 PM] PAPERWORK REDUCTION ACT SUBMISSION ( h) It was developed by an office that has planned and allocated resources for the efficient and effective management and use of the information to be collected ( see note in Item 19 of the instructions);

( I) It uses effective and efficient statistical survey methodology; and ( j) It makes appropriate use of information technology.

If you are unable to certify compliance with any of these provisions, identify the item below and explain the reason in Item 18 of the Supporting Statement.

file:/// C|/ MyStuff/ 1052om06. htm ( 5 of 6) [ 7/ 10/ 03 1: 04: 16 PM] PAPERWORK REDUCTION ACT SUBMISSION Signature of Program Office Official John Rasnic, Director Manufacturing, Energy, and Transportation Division Date Signature of Senior Official or designee Joseph Retzer, Director Regulatory Information Division Office of Regulatory Management and Information ( OPPE) Date OMB 83 I 10/ 95 file:/// C|/ MyStuff/ 1052om06. htm ( 6 of 6) [ 7/ 10/ 03 1: 04: 16 PM]