Document ID: EPA-HQ-OPP-2006-0177-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-12-20T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: September 29, 2006

MEMORANDUM

SUBJECT:	Glyphosate Human Health Risk Assessment for Proposed Use on
Indian Mulberry and Amended Use on Pea, Dry.  PC Code: 417300, Petition
No: 5E6987, DP Num: 321992, Decision No. 360557.

		Regulatory Action: Section 3 Registration Action

		Risk Assessment Type: Single Chemical Aggregate

							

FROM:		    J. R. Tomerlin, PhD, Plant Pathologist

		    Alternative Risk Integration and Assessment Team (ARIA)

		    Fungicide Branch

		    Registration Division (7505P)

THROUGH:   G. F. Kramer, PhD., Senior Chemist

		    Registration Acton Branch 1

		    Health Effects Division (7509P)

			and

		    W. Cutchin, Acting Branch Senior Scientist

		    ARIA Team

		    Technical Review Branch

		    Registration Division (7505P)

TO:		S. Brothers/D. Rosenblatt

		Risk Integration, Minor Use and Emergency Response Branch

		Registration Division (7505P)



Table of Contents

  TOC \f \* MERGEFORMAT \l "1-5"  1.0	Executive Summary	  PAGEREF
_Toc147539444 \h  1 

2.0	Ingredient Profile	  PAGEREF _Toc147539445 \h  3 

2.1	Summary of Registered/Proposed Uses	  PAGEREF _Toc147539446 \h  3 

2.2	Structure and Nomenclature	  PAGEREF _Toc147539447 \h  6 

2.3	Physical and Chemical Properties	  PAGEREF _Toc147539448 \h  6 

3.0	Metabolism Assessment	  PAGEREF _Toc147539449 \h  6 

3.1 	Comparative Metabolic Profile	  PAGEREF _Toc147539450 \h  6 

3.2	Nature of the Residue in Foods	  PAGEREF _Toc147539451 \h  7 

3.2.1.	Description of Primary Crop Metabolism	  PAGEREF _Toc147539452 \h
 7 

3.2.2	Description of Livestock Metabolism	  PAGEREF _Toc147539453 \h  7 

3.2.3	Description of Rotational Crop Metabolism	  PAGEREF _Toc147539454
\h  7 

3.3 	Environmental Degradation	  PAGEREF _Toc147539455 \h  8 

3.4	Toxicity Profile of Major Metabolites and Degradates	  PAGEREF
_Toc147539456 \h  8 

3.5	Summary of Residues for Tolerance Expression and Risk Assessment	 
PAGEREF _Toc147539457 \h  8 

3.5.1	Tabular Summary	  PAGEREF _Toc147539458 \h  8 

4.0     Hazard Characterization/Assessment	  PAGEREF _Toc147539459 \h  9

4.1	Hazard Characterization	  PAGEREF _Toc147539460 \h  9 

4.2	FQPA Hazard Considerations	  PAGEREF _Toc147539461 \h  11 

4.2.1	Adequacy of the Toxicity Data Base	  PAGEREF _Toc147539462 \h  11 

4.2.2	Evidence of Neurotoxicity	  PAGEREF _Toc147539463 \h  11 

4.2.3	Developmental Toxicity Studies	  PAGEREF _Toc147539464 \h  12 

4.2.4	Reproductive Toxicity Study	  PAGEREF _Toc147539465 \h  12 

4.2.6  Pre-and/or Postnatal Toxicity	  PAGEREF _Toc147539466 \h  12 

4.2.6.1  Determination of Susceptibility	  PAGEREF _Toc147539467 \h  13 

4.2.6.2  Degree of Concern Analysis and Residual Uncertainties for Pre
and/or Post-natal Susceptibility	  PAGEREF _Toc147539468 \h  13 

4.3	Recommendation for a Developmental Neurotoxicity Study	  PAGEREF
_Toc147539469 \h  13 

4.3.1	Evidence that supports requiring a Developmental Neurotoxicity
study	  PAGEREF _Toc147539470 \h  13 

4.3.2	Evidence that supports not requiring for a Developmental
Neurotoxicity study		  PAGEREF _Toc147539471 \h  13 

4.4	Hazard Identification and Toxicity Endpoint Selection	  PAGEREF
_Toc147539472 \h  13 

4.4.1   Acute Reference Dose (aRfD) - Females age 13-49	  PAGEREF
_Toc147539473 \h  14 

4.4.2	Acute Reference Dose (aRfD) - General Population	  PAGEREF
_Toc147539474 \h  14 

4.4.3	Chronic Reference Dose (cRfD)	  PAGEREF _Toc147539475 \h  14 

4.4.4	Incidental Oral Exposure (Short and Intermediate Term)	  PAGEREF
_Toc147539476 \h  14 

4.4.5	Dermal Absorption	  PAGEREF _Toc147539477 \h  14 

4.4.6	Dermal Exposure (Short, Intermediate and Long Term)	  PAGEREF
_Toc147539478 \h  14 

4.4.7	Inhalation Exposure (Short, Intermediate and Long Term)	  PAGEREF
_Toc147539479 \h  15 

4.4.8	Margins of Exposure and Levels of Concern	  PAGEREF _Toc147539480
\h  15 

4.4.9	Recommendation for Aggregate Exposure Risk Assessments	  PAGEREF
_Toc147539481 \h  15 

4.4.10	Classification of Carcinogenic Potential	  PAGEREF _Toc147539482
\h  15 

4.5	Special FQPA Safety Factor	  PAGEREF _Toc147539483 \h  17 

4.6	Endocrine disruption	  PAGEREF _Toc147539484 \h  18 

5.0	Public Health Data	  PAGEREF _Toc147539485 \h  18 

5.1	Incident Reports	  PAGEREF _Toc147539486 \h  18 

6.0  Exposure Characterization/Assessment	  PAGEREF _Toc147539487 \h  18

6.1	Dietary Exposure/Risk Pathway	  PAGEREF _Toc147539488 \h  18 

6.1.1	Residue Profile	  PAGEREF _Toc147539489 \h  18 

6.1.2	Acute and Chronic Dietary Exposure and Risk	  PAGEREF
_Toc147539490 \h  20 

6.2	Water Exposure/Risk Pathway	  PAGEREF _Toc147539491 \h  21 

6.3	Residential (Non-Occupational) Exposure/Risk Pathway	  PAGEREF
_Toc147539492 \h  22 

6.3.1	Home Uses	  PAGEREF _Toc147539493 \h  22 

6.3.2	Recreational Uses	  PAGEREF _Toc147539494 \h  24 

6.3.3	Other (Spray Drift, etc.)	  PAGEREF _Toc147539495 \h  25 

7.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF
_Toc147539496 \h  26 

7.1	Acute Aggregate Risk	  PAGEREF _Toc147539497 \h  26 

7.2	Short-and Intermediate-Term Aggregate Risk	  PAGEREF _Toc147539498
\h  26 

7.3	Intermediate-Term Aggregate Risk	  PAGEREF _Toc147539499 \h  27 

7.4	Long-Term Aggregate Risk	  PAGEREF _Toc147539500 \h  27 

7.5	Cancer Risk	  PAGEREF _Toc147539501 \h  27 

8.0	Cumulative Risk Characterization/Assessment	  PAGEREF _Toc147539502
\h  27 

9.0	Occupational Exposure/Risk Pathway	  PAGEREF _Toc147539503 \h  27 

9.1	Short/Intermediate/Long-Term Handler Risk	  PAGEREF _Toc147539504 \h
 27 

9.2	Short/Intermediate/Long-Term Postapplication Risk	  PAGEREF
_Toc147539505 \h  28 

10.0	Data Needs and Label Requirements	  PAGEREF _Toc147539506 \h  28 

10.1	Toxicology	  PAGEREF _Toc147539507 \h  28 

10.2	Residue Chemistry	  PAGEREF _Toc147539508 \h  28 

10.3	Occupational and Residential Exposure	  PAGEREF _Toc147539509 \h 
28 

References	  PAGEREF _Toc147539510 \h  28 

 



1.0	Executive Summary  TC \l1 "1.0	Executive Summary 

The Office of Pesticide Program’s Health Alternative Risk Integration
Assessment (ARIA) team has conducted an aggregate human health risk
assessment for glyphosate.  This assessment includes evaluation of risks
for various population subgroups, including those comprised of infants
and children.  Glyphosate is a broad-spectrum herbicide applied using a
wide range of application methods, including aerial sprays, ground
broadcast sprayers of various types, shielded and hooded sprayers, wiper
applicators, sponge bars, injection systems, and controlled droplet
applicators.  Glyphosate is distributed in several forms, including
glyphosate, the isoproplyamine salt, the diammonium salt, the
ethanolamine salt, or the potassium salt.  This aggregate risk
assessment was prompted by a submission from the Interregional Research
Project No. 4 (IR-4) of field trial data supporting a petition for the
use of glyphosate (N-(phosphonomethyl)glycine) on Indian mulberry, and
amended use patterns on Vegetable, Legume Group 6, except soybeans.

The existing toxicity database for glyphosate is complete and without
data gaps.  There is high confidence in the quality of the existing
studies and the reliability of the toxicity endpoints identified for use
in risk assessment.

Based upon a weight of evidence consideration (see discussion below),
the Agency decided not to require the conduct of a developmental
neurotoxicity study with glyphosate to evaluate the potential for
developmental neurotoxic effects.  Based on developmental studies in
rats and rabbits and reproductive findings in rats, glyphosate exhibited
no evidence of increased qualitative and quantitative susceptibility. 
The developmental No Observed Adverse Effect Level (NOAEL) was 1,000
mg/kg/day in a rat developmental toxicity study.  A developmental
neurotoxicity study was not required.  The Agency concluded that the
effect seen in the three-generation study was a spurious rather than
glyphosate-related effect.  Therefore, the NOAELs for parental,
reproductive or offspring toxicity were 30 mg/kg/day from a 2-generation
rat reproduction study. 

Acute reference doses (RfDs) were not established for either females
13-49 years old, or any population subgroup of the general population
because of the lack of an appropriate toxicological endpoint
attributable to a single dose.  A chronic RfD of 1.75 mg/kg/day was
established based on the NOAEL of 175 mg/kg/day in the rabbit
developmental study.  The Lowest Observed Adverse Effect Level (LOAEL)
of 350 mg/kg/day is based on maternal toxicity.  An RfD of 1.75
mg/kg/day was established on the same study and effect for incidental
oral exposure.  The level of concern was 100 for short-, intermediate-
and long-term incidental oral exposure.  

Endpoints were not established for (short-, intermediate- and long-term)
dermal exposures because of the lack of hazard in the 21-day rabbit
dermal toxicity study.  Likewise, endpoints were not established for
(short-, intermediate- and long-term) inhalation exposures because of
the lack of hazard in the 28-day rat inhalation toxicity study.

Glyphosate has been classified as a Group E carcinogen with no evidence
of human carcinogenicity.  Therefore, a cancer risk assessment is not
required for glyphosate.

The Agency decided that the Food Quality Protection Act (FQPA) safety
factor of 10x be removed (reduced to 1x) because there is no evidence of
quantitative or qualitative increased susceptibility of the young
demonstrated in the prenatal developmental studies in rats and rabbits
and pre/post natal reproduction study in rats.  Furthermore, the
toxicology data base is complete.  Finally, a developmental
neurotoxicity study is not required; and the dietary (food and drinking
water) exposure assessments will not underestimate the potential
exposures for infants and children.

The nature of glyphosate residues in both plants and livestock is
adequately understood.  Glyphosate per se is the only toxicologically
significant residue.  The Agency has previously determined that, based
on toxicological considerations, AMPA need not be regulated regardless
of levels observed in foods or feeds.  Consequently, the terminal
residue to be regulated in plants and livestock is glyphosate per se.

The IR-4 submitted field trial data for glyphosate on dry peas.  In all
trials, Roundup Ultra® Herbicide was applied to preemergence plants,
with a second foliar application 7 days before harvest; registration is
being sought for Roundup WeatherMax®.  A total of 5.89-6.01 lb a.i./A
(6.7 kg a.i./hectare) of compound was applied per season in the dry pea
trials, approximately 75% of the proposed label rate for WeatherMax®. 
The treatment interval was 91 days in the dry pea trials.  The number
and locations of dry pea field trials are in accordance with OPPTS
Guideline 860.1500.  No field trial residue data were submitted for the
proposed use on Indian mulberry; however, ARIA concludes that the use on
Indian mulberry is analogous to the existing use on Tropical and
Subtropical Trees and Fruits, and that the existing data for sugar apple
may be applied to Indian mulberry.

Samples of dry pea were analyzed for residues of glyphosate using an
HPLC/FLD (High Pressure Liquid Chromatography/Fluorescence Detector)
method.  The validated Limit of Quantitation (LOQ) was 0.05 ppm, and the
LOD (Limit of Detection) was 0.025 ppm.  This method is adequate for
data collection based on acceptable method validation and concurrent
recovery data.  The results from the dry pea field trials show that
residues in dry pea harvested 7 days following preplant + harvest aid
application at a total seasonal rate of 4.42-4.51 lb ae/A (5.89-6.01 lb
a.i./A) were 0.59-3.57 ppm.  Residues in two samples of dry pea
harvested 7 days following a single harvest aid application at 2.21 lb
ae/A (2.95 lb a.i./A) were 2.20 and 6.19 ppm.  

The Maximum Residue Limit (MRL) Spreadsheet Calculator was used to
estimate recommended glyphosate tolerances in dry peas.  The petitioner
proposed a tolerance of 8.0 ppm for Vegetable, Legume, Group 6, except
soybean.  The spreadsheet confirms the tolerance value of 8.0 ppm based
upon the data set from the residue field trials; however, the data only
support a tolerance of 8.0 ppm on pea, dry.  Therefore, ARIA recommended
for the requested glyphosate tolerance of 8.0 ppm on pea, dry, not the
entire Vegetable Legume, Group 6, except soybean.

For crop applications, the acute and chronic estimated environmental
concentration (EEC) for ground water is 0.0038 ppb (from Tier I
Screening Concentration in Ground Water (SCI-GROW) modeling).  The acute
(peak) and chronic (56-day average, including 3X adjustment factor) EECs
for surface water (from Tier I (Generic Estimated Exposure Concentration
(GENEEC) modeling) are 21 ppb and 0.83 ppb, respectively.  The EEC
resulting from the registered use of direct glyphosate application to
surface water is 230 ppb,
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瑮慲楴湯⠠坄䍅⸩ഠ

A Tier 1 chronic dietary analysis for glyphosate was conducted using the
Dietary Exposure Evaluation Model (DEEM-FCID™) with tolerance level
residues and 100% crop treated.  The DWEC of 230 ppb in water were used
directly in the DEEM dietary exposure analysis.  The exposure estimate
of the U.S. population is 2% of the chronic population adjusted dose
(PAD; cPAD).  The exposure estimate for the most highly exposed
subpopulation (all infants <1 year old) is 7% of the cPAD.   

Margins of Exposure (MOEs) ranged from 1400 (non-nursing infants < one
year) to 4510 (adults 20 to 49 years) for short- and intermediate-term
aggregate risk.  Therefore, short- and inter-mediate term aggregate risk
is below the Agency’s level of concern.

Long-term chronic risk does not include estimates of residential risk. 
Furthermore, water residues were incorporated into the chronic dietary
risk assessment, so in effect, the chronic dietary risk assessment also
provides the estimate of long-term aggregate risk.  Long-term aggregate
risk does not exceed the Agency’s level of concern.

Previous risk assessments have requested the petitioner to submit
revised supplemental labels to include 30-day plant back restriction for
rotational crops.  After reconsideration, ARIA concludes that the
current language in the Glyphosate WeatherMax™ label (section 8.0) is
sufficient with respect to plant back restrictions.  ARIA recommends
that the proposed tolerance be revised to reflect the correct tolerance
expression: glyphosate N-(phosphonomethyl)glycine resulting from the
application of glyphosate, the isopropylamine salt of glyphosate, the
ethanolamine salt of glyphosate, the ammonium salt of glyphosate, and
the potassium salt of glyphosate.  Given these considerations, ARIA
recommends for the establishment of tolerances for the residues of
glyphosate of 0.20 ppm in/on Indian mulberry and of 8.0 ppm in/on pea,
dry.  The existing tolerance of 5.0 ppm for “Vegetable, legume, group
6, except soybean” should be revised to apply to “Vegetable, legume,
group 6 except soybean and pea, dry.”

2.0	Ingredient Profile  TC \l1 "2.0	Ingredient Profile 

Glyphosate is a broad-spectrum herbicide applied using a wide range of
application methods, including aerial sprays, ground broadcast sprayers
of various types, shielded and hooded sprayers, wiper applicators,
sponge bars, injection systems, and controlled droplet applicators. 
Glyphosate is distributed in several forms, including glyphosate, the
isoproplyamine salt, the diammonium salt, the ethanolamine salt, or the
potassium salt.

2.1	Summary of Registered/Proposed Uses  TC \l2 "2.1	Summary of
Registered/Proposed Uses 

The tolerance expression as stated in 40 CFR 180.364 is glyphosate
(N-(phosphonomethyl)glycine).  

The IR-4 has proposed adding Indian mulberry to the exiting use pattern
for glyphosate on Tropical and Subtropical Trees and Fruits and also
submitted field trial data to amend the existing use patterns on
Vegetable, Legume Group 6, except soybean.  The proposed use patterns
are summarized in Table 2.1.

Table 2.1.	Summary of Directions for Use of Glyphosate.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate

(lb ai/A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate (lb
ai/A)	PHI (days)	Use Directions and Limitations

Indian Mulberry

Preplant (site preparation) broadcast spray	524-537	3.7	Not specified
7.9	14	An application for site preparation may be made prior to planting
or transplanting.  In addition, applications may be made to established
plantings in middles (between rows of trees or vines), strips (within
rows of trees or vines), and for general weed control or perennial grass
suppression and cut stump.  Applications are to be made in spray volumes
of 3-40 gal/A using ground equipment including selective equipment
(shielded sprayers or wiper treatment).

Post-emergence/

Established:  directed sprays, spot treatment

Ground	524-537	3.7	Not specified	7.9	14

	Pea, Dry

Broadcast foliar

Ground or aerial	524-537	2.25	1	2.25	7	Application is to be made
over-the-top prior to the harvest of dry peas.  Apply  to
physiologically mature peas (hard dough stage of the legume seed; 30%
grain moisture or less) in spray volumes of 3-40 gal/A for ground
equipment and 3-15 gal/A for aerial equipment.  Do not combine
preharvest spray with a spot treatment on same crop area.  Feeding
treated vines and hay to livestock is prohibited.  Treatment of field
(feed) peas grown for livestock feed is prohibited.

Spot treatment

Ground	524-537	2.25	1	2.25	7	Application is to be made in spray volumes
of 10-20 gal/A using ground equipment or as a 2% solution using a
handheld sprayer.  Applications should be made at or beyond the bud
stage of growth.  Do not combine spot treatments with a preharvest
broadcast spray on same crop area.  The crop receiving spray in treated
areas will be killed.  Feeding treated vines and hay to livestock is
prohibited.  Treatment of field (feed) peas grown for livestock feed is
prohibited

Structure and Nomenclature  TC \l2 "2.2	Structure and Nomenclature 

 

Empirical Formula	C3H8NO5P

Common name	Glyphosate

Company experimental name	MON 65005

IUPAC name	N-(phosphonomethyl)glycine

CAS name	Glycine, N-(phosphonomethyl)

CAS Registry Number	1071-83-6

End-use product/EP	Roundup Ultra® Herbicide

2.3	Physical and Chemical Properties  TC \l2 "2.3	Physical and Chemical
Properties 

Table 2.3.	Physicochemical Properties

Parameter	Value	Reference

Molecular Weight	169.08	Extoxnet

Melting point/range	185.5 C	FAO Specifications and Evaluations

pH	4.2 to 5.8 15 g/l	Monsanto.com

Density	1.7 @ 20 C	IPCS

Water solubility (20 C)	10,100 mg/L @ 20 C	IPCS

Solvent solubility (temperature not specified)	Insoluble in most organic
solvents	Extoxnet

Vapor pressure (25 C)	< 1 x 10-5 Pa @ 25 C	IPCS

Dissociation constant, pKa	< 2, 2.6, 5.6, 10.6	IPCS

Octanol/water partition coefficient, logPOW (25 C)	-2.8	IPCS

UV/visible absorption spectrum	12,000	IPCS

3.0	Metabolism Assessment  TC \l1 "3.0	Metabolism Assessment 

3.1 	Comparative Metabolic Profile  TC \l2 "3.1 	Comparative Metabolic
Profile 

In the rat metabolism study, absorption was estimated to be 30-36% in
males and females.  Glyphosate was excreted unchanged in the feces and
urine (97.5% minimum).  The only metabolite present in the excreta was
small amounts of AMPA.  Less than 1% of the absorbed dose remained in
the carcass, primarily the bone.  Repeated dosing did not alter
metabolism, distribution, and excretion.

3.2	Nature of the Residue in Foods  TC \l2 "3.2	Nature of the Residue in
Foods 

3.2.1.	Description of Primary Crop Metabolism  TC \l3 "3.2.1.
Description of Primary Crop Metabolism 

Studies with a variety of plants including corn, cotton, soybeans, and
wheat indicate that the uptake of glyphosate or its metabolite, AMPA,
from soil is limited.  The material that is taken up is readily
translocated.  Foliar-applied glyphosate is readily absorbed and
translocated throughout the trees or vines to the fruit of apples,
coffee, dwarf citrus (calamondin), pears and grapes.  Metabolism via
N-methylation yields N-methylated glycines and phosphonic acids.  For
the most part, the ratio of glyphosate to AMPA is 9 to 1 but can
approach 1 to 1 in a few cases (e.g., soybeans and carrots).  Much of
the residue data for crops reflects a detectable residue of parent (0.05
- 0.15 ppm) along with residues below the level of detection (<0.05 ppm)
of AMPA (Memo, R. Perfetti, 10/27/92).  The HED Metabolism Committee
determined that, based on toxicological considerations, AMPA need not be
regulated and should be dropped from the tolerance expression (Memo, R.
Perfetti, 10/19/92).  Furthermore, in a 3/17/94 meeting, the HED
Metabolism Committee discussed whether uses that result in significantly
higher residues of AMPA in plants and livestock commodities in the
future would require that AMPA be reintroduced into the tolerance
expression of glyphosate.  The Committee determined that, based on
toxicological considerations, AMPA need not be regulated regardless of
levels observed in foods or feeds (Memo, R. Perfetti, 3/17/94).

Metabolism studies submitted for genetically engineered
glyphosate-tolerant canola (DP Nums: 242628 and 245591, T. Bloem,
11/30/98) and glyphosate-tolerant corn (DP Num: 217539, G. Kramer,
3/14/96) have indicated that metabolism in glyphosate-tolerant plants is
essentially the same as that in normal plants.  Thus, the terminal
residue to be regulated in plants is glyphosate per se.

3.2.2	Description of Livestock Metabolism  TC \l3 "3.2.2	Description of
Livestock Metabolism 

Studies with lactating goats and laying hens fed a mixture of glyphosate
and AMPA indicate that the primary route of elimination was by excretion
(urine and feces).  These results are consistent with metabolism studies
in rats, rabbits, and cows.  The terminal residues in eggs, milk, and
livestock tissues are glyphosate and its metabolite AMPA; there was no
evidence of further metabolism (Memo, R. Perfetti, 10/27/92).  The
conclusions of the HED Metabolism Committee on 10/19/92 and 3/17/94
apply to plant and livestock commodities.  Thus, the terminal residue to
be regulated in livestock is glyphosate per se.

3.2.3	Description of Rotational Crop Metabolism  TC \l3 "3.2.3
Description of Rotational Crop Metabolism 

A previously reviewed confined crop rotational study (Memo; MRIDs
41543201 and 41543202, A. Abramovitch, 10/14/92) indicated that residues
of glyphosate were not detectable in crops planted 30 days after
treatment. 

3.3 	Environmental Degradation  TC \l2 "3.3 	Environmental Degradation 

DP Num: 280831, W. H. Donovan, W. G. Dykstra and J. T. Swackhammer,
2/20/02

HED does not have ground or surface water monitoring data to calculate
quantitative aggregate exposure.  Consequently, estimates of glyphosate
levels in surface and ground water were made using computer modeling. 
EFED provided a drinking water assessment of glyphosate for direct
application to water and for application to crops.  For crop
applications, the acute and chronic EEC for ground water is 0.0038 ppb
(from Tier I SCI-GROW modeling).  The acute (peak) and chronic (56-day
average, including 3X adjustment factor) EECs for surface water (from
Tier I GENEEC modeling) are 21 ppb and 0.83 ppb, respectively.  The EEC
resulting from the registered use of direct glyphosate application to
surface water is 230 ppb.  

3.4	Toxicity Profile of Major Metabolites and Degradates   TC \l2 "3.4
Toxicity Profile of Major Metabolites and Degradates  

The residue of concern for risk assessment purposes is glyphosate per
se.  The metabolite   AMPA is not included in either the tolerance
expression or the risk assessment.  Much of the residue data for crops
reflects a detectable residue of parent (0.05 - 0.15 ppm) along with
residues below the level of detection (<0.05 ppm) of AMPA (Memo, R.
Perfetti, 10/27/92).  In a meeting of the HED Metabolism Committee held
8/19/92, the Committee determined that, based on toxicological
considerations, AMPA need not be regulated and should be dropped from
the tolerance expression (Memo, R. Perfetti, 10/10/92).  Furthermore, in
a meeting of the HED Metabolism Committee held 3/17/94, the Committee
discussed whether uses that result in significantly higher residues of
AMPA in plants and livestock commodities in the future would require
that AMPA be reintroduced into the tolerance expression of glyphosate. 
The Committee determined that, based on toxicological considerations,
AMPA need not be regulated regardless of levels observed in foods or
feeds (Memo, R. Perfetti, 3/17/94).

3.5	Summary of Residues for Tolerance Expression and Risk Assessment  TC
\l2 "3.5	Summary of Residues for Tolerance Expression and Risk
Assessment 

3.5.1	Tabular Summary  TC \l3 "3.5.1	Tabular Summary 

Table 3.5.1.	Summary of Metabolites and Degradates to be included in the
Risk Assessment and Tolerance Expression

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants	Primary Crop	glyphosate (N-(phosphonomethyl)glycine)	glyphosate
(N-(phosphonomethyl)glycine)

	Rotational Crop

Livestock	Ruminant

	Poultry

Drinking Water

Not Applicable

4.0	Hazard Characterization/Assessment  TC \l1 "4.0  Hazard
Characterization/Assessment 

4.1	Hazard Characterization  TC \l2 "4.1	Hazard Characterization 

The existing toxicity database for glyphosate is complete and without
data gaps.  There is high confidence in the quality of the existing
studies and the reliability of the toxicity endpoints identified for use
in risk assessment.

Glyphosate  is of low acute toxicity by oral, dermal, and ocular routes
of exposure, since all studies are in Toxicity Category III or IV. 
Glyphosate is a mild skin irritant (Toxicity Category IV), and is not a
dermal sensitizer in guinea pigs.  Systemic toxicity was not observed 
in a 21 day dermal toxicity study in rats up to the limit dose (1,000
mg/kg/day).  An upper bound dermal penetration of 35% was estimated by
the extrapolation method of comparing the maternal toxicity LOAEL of 350
mg/kg/day for the rabbit oral developmental toxicity study and the
systemic NOAEL of 1,000 mg/kg/day in the 21 day dermal toxicity study. 

In the rat metabolism study, absorption was estimated to be 30-36% in
males and females.  Glyphosate was excreted unchanged in the feces and
urine (97.5% minimum). The only metabolite present in the excreta was
small amounts of AMPA.  Less than 1% of the absorbed dose remained in
the carcass, primarily the bone.  Repeated dosing did not alter
metabolism, distribution, and excretion

Table 4.1a	Acute Toxicity Profile - Test Substance 

Guideline No.	Study Type	MRID(s)	Results	Toxicity Category

870.1100	Acute oral	41400601	LD50 > 5,000 mg/kg	IV

870.1200	Acute dermal 	41400602	LD50 > 5,000 mg/kg	IV

870.1300	Acute inhalation 	None	The requirement for an acute inhalation
LC50 study was waived	None

870.2400	Acute eye irritation 	41400603	Corneal opacity or irritation
clearing in 7 days or less	III

870.2500	Acute dermal irritation 	41400604	Mild or slight irritant	IV

870.2600	Skin sensitization 	41642307	Not a sensitizer	None

Table 4.1b	Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type	Results

870.3100

90-Day oral toxicity (Mouse)	NOAEL = 1500 mg/kg/day in males and females

LOAEL = 4500 mg/kg/day in males and females based on decreased body
weight.

870.3100

90-Day oral toxicity (Range finding)	NOAEL = not established

LOAEL = 50 mg/kg/day in males and females based on possible increased
phosphorus and potassium values.

870.3150

90-Day oral toxicity (Rat) - Aminomethyl phosphoric acid - glyphosate
plant metabolite	NOAEL = 400 mg/kg/day in males and females

LOAEL = 1200 mg/kg/day in males and females based on body weight loss
and histopathological lesions of the urinary bladder.

870.3200

21/28-Day dermal toxicity (Rabbit)	NOAEL = 1000 mg/kg/day in males and
females

LOAEL = 5000 mg/kg/day based on slight erythema and edema on intact and
abraded skin of both sexes, and decreased food consumption in females.

870.3485

28-Day inhalation toxicity (rat)	NOAEL = 0.36 mg/L (HDT); LOAEL not
established based on 6 hours/day, 5 days/week for 4 weeks

870.3700a

Prenatal developmental in rodents (Rat)	Maternal NOAEL = 1000 mg/kg/day

LOAEL = 3500 mg/kg/day based on inactivity, mortality, stomach
hemorrhages and reduced body weight gain.

Developmental NOAEL = 1000 mg/kg/day

LOAEL = 3500 mg/kg/day based on increased incidence in the number of
fetuses and litters with unossified sternebrae and decreased fetal body
weight.

870.3700b

Prenatal developmental in (Rabbit)	Maternal NOAEL = 175 mg/kg/day

LOAEL = 350 mg/kg/day based on mortality, diarrhea, soft stools, and
nasal discharge.

Developmental NOAEL = 350 mg/kg/day (HDT)

LOAEL = not established.

870.3800

Reproduction and fertility effects, 3-generation (Rat)	Parental/Systemic
NOAEL = 30 mg/kg/day (HDT)

Reproductive NOAEL = 30 mg/kg/day (HDT)

Offspring NOAEL = 10 mg/kg/day

LOAEL = 30 mg/kg/day based on focal dilation of the kidney in male F3b
pups.

870.3800

Reproduction and fertility effects, 2-generation (Rat)	Parental/Systemic
NOAEL = 500 mg/kg/day in males and females

LOAEL = 1500 mg/kg/day in males and females based on soft stools,
decreased body weight gain and food consumption.  Focal dilation of the
kidney observed at 30 mg/kg/day in the 3-generation study was not
observed at any dose level in this study.

Reproductive NOAEL ( 1500 mg/kg/day (HDT) in males and females

Offspring NOAEL = 500 mg/kg/day in males and females

LOAEL = 1500 mg/kg/day in males and females based on decreased body
weight gain during lactation.

870.4100b

Chronic toxicity (dog)	NOAEL = 500 mg/kg/day in males and females (HDT)

LOAEL = not established.

870.4300

Carcinogenicity

(Mice)	NOAEL = 750 mg/kg/day in males and females

LOAEL = 4500 mg/kg/day in males and females based on significant
decreased body weight gain in both sexes, hepatocyte necrosis and
interstitial nephritis in males, and increased incidence of proximal
tubule epithelial basophilia and hypertrophy in the kidney of females.

No evidence of carcinogenicity

870.4300

Chronic/Carcino-genicity (Rat)	NOAEL = 362 mg/kg/day in males, 447
mg/kg/day in females

LOAEL = 940 mg/kg/day in males, 1183 mg/kg/day in females based on
decreased body weight gain in females, decreased urinary pH in males,
increased incidence of cataracts and lens abnormalities in males, and
increased absolute and relative (to brain) liver weight in males.

No evidence of carcinogenicity

Gene Mutation

870.5265	Non-mutagenic when tested up to 1000 ug/plate, in presence and
absence of activation in S. typhimurium strains TA98, TA100, TA1535 and
TA1537.

Gene Mutation

870.5300	Non-mutagenic at the HGPRT locus in Chinese hamster ovary cells
tested up to cytotoxic concentrations or limit of solubility, in
presence and absence of activation.

In Vivo Cytogenetics - Bone Marrow 870.5385	Non-mutagenic in rat bone
marrow chromosome assay up to 1000 mg/kg in both sexes of Sprague Dawley
rats.

870.5550

 Rec - Assay and Gene Mutation Assay 

	There was no evidence of recombination in the rec-assay up to 2,000
ug/disk with B. subtilis H17 (rec+) and M45 (rec-).  Negative for
reverse gene mutation, both with and without S-9, up to 5,000 ug/plate
(or cytotoxicity) with E.coli SP2hcrA and S. typhimuarium TA98, TA100,
TA1535, TA1537, and TA1538.

870.7485

Metabolism and pharmacokinetics

(Rat)	Absorption was 30-36% in males and females.  Glyphosate was
excreted unchanged in the feces and urine (97.5% minimum).  The only
metabolite present in the excreta was AMPA.  Less than 1% of the
absorbed dose remained in the carcass, primarily bone.  Repeat dosing
did not alter metabolism, distribution, and excretion.

4.2	FQPA Hazard Considerations  TC \l2 "4.2	FQPA Hazard Considerations 

4.2.1	Adequacy of the Toxicity Data Base  TC \l3 "4.2.1	Adequacy of the
Toxicity Data Base 

The toxicology database for glyphosate is adequate according to the
Subdivision F Guideline requirements for a food-use chemical. 
Acceptable developmental toxicity studies in the rat and rabbit are
available, as is an acceptable 2-generation reproduction study in the
rat.  

4.2.2	Evidence of Neurotoxicity  TC \l3 "4.2.2	Evidence of Neurotoxicity

There was no evidence of neurotoxicity in any of the toxicology studies
conducted, and there are no data requirements for neurotoxicity studies.
 Since glyphosate lacks a leaving group, it would not seem likely to
inhibit esterases, which is the presumptive neurotoxic mechanism of
concern for all organophosphates (HIARC Doc. TXR#0050428, 1/22/02; HIARC
= Hazard Identification Assessment Review Committee).  Based upon a
weight of evidence consideration (see discussion below), the Committee
decided not to require the conduct of a developmental neurotoxicity
study with glyphosate to evaluate the potential for developmental
neurotoxic effects.

4.2.3	Developmental Toxicity Studies  TC \l3 "4.2.3	Developmental
Toxicity Studies 

The NOAEL of 175 mg/kg/day for maternal toxicity based on mortality,
diarrhea, and nasal discharge at the LOAEL of 350 mg/kg/day in the
rabbit developmental study was the lowest NOAEL of all the major
studies.  On the basis of developmental studies in rats and rabbits and
reproductive findings in rats, glyphosate exhibited no evidence of
increased qualitative and quantitative susceptibility.  A developmental
neurotoxicity study was not required.  

In rats, developmental effects consisting of unossified sternebrae and
decreased fetal body weight were observed at a LOAEL of 3,500 mg/kg/day
which was also the LOAEL for maternal toxicity. The maternal NOAEL was
1,000 mg/kg/day based on mortality, decreased body weight gain,
diarrhea, inactivity, red matting on nose, mouth, forelimbs, and head,
decrease in total implantations/dam and nonviable fetuses/dam.  The
developmental NOAEL was 1,000 mg/kg/day.  In rabbits, the maternal
NOAEL/LOAEL was 175/350 mg/kg/day based on increased mortality (does)
and clinical signs.  The developmental NOAEL was 350 mg/kg/day (HDT). 

4.2.4	Reproductive Toxicity Study  TC \l3 "4.2.4	Reproductive Toxicity
Study 

There were no reproductive toxicity concerns relevant to the dermal and
inhalation toxicity.  In the 2-generation rat reproduction study, the
offspring and parental NOAELs were 500 mg/kg/day based on decreased pup
body weight during lactation (offspring) and soft stools, decreased body
weight and food consumption (parents) at the LOAEL of 1500 mg/kg/day. 
The reproductive NOAEL was  1500 mg/kg/day (HDT).  In a
three-generation rat reproduction study, the only effect observed in the
study was an increased incidence of focal tubular dilation of the kidney
(both unilateral and bilateral combined) in the high-dose male F3b pups
at 30 mg/kg/day (HDT).  However, this effect (focal tubular dilation of
the kidneys) was not observed at the 1500 mg/kg/day level in a
subsequent 2-generation rat reproduction study.  Therefore, the HED
RfD/Peer Review Committee and the Risk Assessment Review Committee
(RARC) concluded that the effect seen in the three generation study was
a spurious rather than glyphosate-related effect.  Therefore, the NOAELs
for parental, reproductive or offspring toxicity were 30 mg/kg/day. 

4.2.5  Pre-and/or Postnatal Toxicity  TC \l3 "4.2.6  Pre-and/or
Postnatal Toxicity 

Based on the acceptable developmental studies, the Agency has determined
that there is no evidence of either a quantitative or qualitative
increased susceptibility following in utero glyphosate exposure to rats
or rabbits, or following prenatal/postnatal exposure in the 2-
generation reproduction study in rats.  There is no evidence of
quantitative or qualitative increased susceptibility of the young
demonstrated in the prenatal developmental studies in rats or rabbits
and pre-/postnatal reproduction study in rats; and the dietary (food and
drinking water) exposure assessments will not underestimate the
potential exposure for infants and children.

4.2.5.1  Determination of Susceptibility  TC \l4 "4.2.6.1  Determination
of Susceptibility 

On the basis of developmental studies in rats and rabbits and
reproductive findings in rats, glyphosate exhibited no evidence of
increased qualitative and quantitative susceptibility.  A developmental
neurotoxicity study was not required.

4.2.5.2  Degree of Concern Analysis and Residual Uncertainties for Pre
and/or Post-natal Susceptibility  TC \l4 "4.2.6.2  Degree of Concern
Analysis and Residual Uncertainties for Pre and/or Post-natal
Susceptibility 

A developmental neurotoxicity study was not required, based on
observations from developmental studies in rats and rabbits and
reproductive findings in rats that glyphosate exhibited no evidence of
increased qualitative and quantitative susceptibility.  Based on the
available data, there was no evidence of quantitative or qualitative
increased susceptibility following in utero glyphosate exposure to rats
and rabbits, or following pre/post natal exposure in the 2-generation
reproduction study in rats.

4.3	Recommendation for a Developmental Neurotoxicity Study  TC \l2 "4.3
Recommendation for a Developmental Neurotoxicity Study 

On the basis of developmental studies in rats and rabbits and
reproductive findings in rats, glyphosate exhibited no evidence of
increased qualitative and quantitative susceptibility.  A developmental
neurotoxicity study was not required.  Therefore, based upon a weight of
evidence consideration, the Agency decided not to require the conduct of
a developmental neurotoxicity study with glyphosate to evaluate the
potential for developmental neurotoxic effects.

4.3.1	Evidence that supports requiring a Developmental Neurotoxicity
study  TC \l3 "4.3.1	Evidence that supports requiring a Developmental
Neurotoxicity study 

There is not any evidence that supports requiring a developmental
neurotoxicity study.

4.3.2	Evidence that supports not requiring for a Developmental
Neurotoxicity study  TC \l3 "4.3.2	Evidence that supports not requiring
for a Developmental Neurotoxicity study 

There was no evidence of neurotoxic clinical signs or neuropathology in
any of the available studies.  Furthermore, there was no evidence of
qualitative or quantitative increased susceptibility in rat and rabbit
developmental studies or in the 2-generation rat reproduction study. 
Finally, there was no additional information in the open literature
indicating that a developmental neurotoxicity study is warranted.

4.4	Hazard Identification and Toxicity Endpoint Selection  TC \l2 "4.4
Hazard Identification and Toxicity Endpoint Selection 

Glyphosate endpoints for risk assessment are summarized in Table 4.4.10.

4.4.1	Acute Reference Dose (aRfD) - Females age 13-49  TC \l3 "4.4.1  
Acute Reference Dose (aRfD) - Females age 13-49 

An acute reference dose (aRfD) was not established for females age
13-49, based on the absence of an appropriate toxicological endpoint
attributable to a single exposure (dose), including maternal toxicity in
developmental toxicity studies. 

4.4.2	Acute Reference Dose (aRfD) - General Population  TC \l3 "4.4.2
Acute Reference Dose (aRfD) - General Population 

An acute reference dose (aRfD) was not established for any population
subgroup or the general population, including infants and children,
based on the absence of an appropriate toxicological endpoint
attributable to a single exposure (dose), including maternal toxicity in
developmental toxicity studies. 

4.4.3	Chronic Reference Dose (cRfD)  TC \l3 "4.4.3	Chronic Reference
Dose (cRfD) 

Study Selected: Developmental toxicity study in rabbits

Dose and Endpoint for Establishing cRfD:  LOAEL=350 mg/kg/day, based on
maternal toxicity.  A NOAEL of 175 mg/kg/day was determined for this
study.

Uncertainty Factor(s):  UF=100 (10x for intraspecies and 10x for
interspecies variation).

Comments about Study/Endpoint/Uncertainty Factor: The NOAEL selected was
the lowest one observed in all of the major toxicity studies.

100 (UF) = 1.75 mg/kg/day

4.4.4	Incidental Oral Exposure (Short and Intermediate Term)  TC \l3
"4.4.4	Incidental Oral Exposure (Short and Intermediate Term) 

Study Selected: Developmental toxicity study in rabbits 

Dose and Endpoint for Establishing cRfD:  LOAEL=350 mg/kg/day, based on
maternal toxicity.  A NOAEL of 175 mg/kg/day was determined for this
study.

Uncertainty Factor(s):  UF=100 (10x for intraspecies and 10x for
interspecies variation).

Comments about Study/Endpoint/Uncertainty Factor: The NOAEL selected was
the lowest one observed in all of the major toxicity studies.

RfD  = 175 mg/kg/day (LOAEL) ÷ 100 (UF) = 1.75 mg/kg/day

4.4.5	Dermal Absorption  TC \l3 "4.4.5	Dermal Absorption 

As discussed in section 4.4.6, dermal endpoints for glyphosate were not
selected.  Consequently, dermal absorption does not need to be addressed
in the risk assessment.

4.4.6	Dermal Exposure (Short, Intermediate and Long Term)  TC \l3 "4.4.6
Dermal Exposure (Short, Intermediate and Long Term) 

Short-, intermediate- and long-term dermal endpoints were not selected
based on the absence of hazard in the 21-day dermal toxicity study in
rabbits.  Additionally, there were no developmental or reproductive
toxicity concerns relevant to dermal endpoint selection. 

4.4.7	Inhalation Exposure (Short, Intermediate and Long Term)  TC \l3
"4.4.7	Inhalation Exposure (Short, Intermediate and Long Term) 

Short-, intermediate- and long-term inhalation endpoints were not
selected based on the absence of hazard in the 28-day inhalation
toxicity study in rats.  Additionally, there were no developmental or
reproductive toxicity concerns relevant to inhalation endpoint
selection. 

4.4.8	Margins of Exposure and Levels of Concern  TC \l3 "4.4.8	Margins
of Exposure and Levels of Concern  

The levels of concern (LOC) for residential risk assessment are 100 for
short-, intermediate- and long-term inhalation exposures.

4.4.9	Recommendation for Aggregate Exposure Risk Assessments  TC \l3
"4.4.9	Recommendation for Aggregate Exposure Risk Assessments 

4.4.10	Classification of Carcinogenic Potential  TC \l3 "4.4.10
Classification of Carcinogenic Potential 

Glyphosate has been classified by the HED Cancer Peer Review Committee
as "a Group E" chemical- negative as a human carcinogen - based on the
absence of carcinogenicity in mice and rats (TXR#: 008898, 12/16/91). 
In the 2- year chronic toxicity/carcinogenicity rat feeding study, the
results showed a slightly increased incidence of pancreatic islet cell
adenomas in the low and high dose males; hepatocellular adenomas in the
low and high dose males; and thyroid C-cell adenomas in the mid and high
dose males and females.  The Agency concluded that these adenomas were
not treatment-related and glyphosate was not considered to be
carcinogenic in this study. The pancreatic islet cell adenomas did not
display a positive dose-trend in their occurrence; there was no
progression to carcinoma and the incidence of pancreatic hyperplasia was
not dose-related.  The hepatocellular adenomas were not statistically
significant by pair-wise comparison; the incidence was within the range
of historical controls; there was no progression to carcinoma and the
hyperplasia was not compound-related.  The C-cell adenomas were
statistically significant by pair-wise comparison and were not
dose-related; there was no progression to carcinoma and there was no
significant dose-related increase in severity or incidence of
hyperplasia in either sex.

In the 2-year carcinogenicity study in mice, the incidence in males of
renal tubular adenomas, a rare tumor, was 1, 0, 1, and 3 in the control,
low, mid, and high dose groups, respectively.  Although the trend was
significant, there was no statistical significance by pairwise
comparison of the control and high dose group.  The incidence at the
high dose exceeded the occurrence of historical controls from the
testing laboratory.  The non-neoplastic findings in the male kidney did
not occur in an increased dose-related manner and the tumorigenic
findings in the kidney were considered to occur by chance rather than
because of treatment. 



Table 4.4.10.	Summary of Toxicological Doses and Endpoints for Chemical
for Use in Human Health Risk Assessments

Exposure

Scenario	Dose Used in Risk Assessment, UF 	Special FQPA SF* and Level of
Concern for Risk Assessment	Study and Toxicological Effects

Acute Dietary,

Females 13-49 and all seg-ments of the general popula-tion	None	None	An
acute dietary endpoint was not selected for the general population or
females 13-50, since an appropriate endpoint attributable to a single
exposure was not identified in the toxicology data base.

Chronic Dietary

(all populations)	NOAEL= 175 mg/kg/day

UF = 100

Chronic RfD = 1.75 mg/kg/day	FQPA SF = 1X 

cPAD = cRfD

             FQPA SF

= 1.75 mg/kg/day	Developmental Toxicity Study - rabbit

LOAEL = 350 mg/kg/day based on diarrhea, nasal discharge and death in
maternal animals

Short-, and Intermediate-Term Incidental, Oral

 (Residential)	NOAEL = 175 mg/kg/day	LOC for MOE = 100	Developmental
Toxicity Study - rabbit

LOAEL = 350 mg/kg/day based on diarrhea, nasal discharge and death in
maternal animals

Short-, Intermediate- and Long-Term

Dermal (1 - 30 days, 1-6 months, 6 months -lifetime )

(Occupational/Residential)	None	None	Based on the systemic NOAEL of
1,000 mg/kg/day in the 21 day dermal toxicity study in rabbits, and the
lack of concern for developmental and reproductive effects, the
quantification of dermal risks is not required.

Short-, Intermediate- and Long-Term Inhalation (1-30 days, 1- 6 months,
6 months-lifetime)

(Occupational/Residential)	None	None	Based on the systemic toxicity
NOAEL of 0.36 mg/L (HDT) in the 28-day inhalation toxicity study in
rats, and the physical characteristics of the technical (wetcake), the
quantification of inhalation risks is not required.

Cancer (oral, dermal, inhalation)	Classification: Group E; no evidence
of carcinogenicity; risk assessment not required

UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL =
no observed adverse effect  level, LOAEL = lowest observed adverse
effect level, PAD = population adjusted dose (a = acute, c = chronic)
RfD = reference dose, MOE = margin of exposure, LOC = level of concern,
NA = Not Applicable

* Refer to Section 4.5

4.5	Special FQPA Safety Factor					  TC \l2 "4.5	Special FQPA Safety
Factor					 

The FQPA Safety Factor Committee (SFC) met on April 6, 1998 to evaluate
the hazard and exposure data for glyphosate.  The toxicology database
for glyphosate is adequate according to the Subdivision F Guideline
requirements for a food-use chemical.  Acceptable developmental toxicity
studies in the rat and rabbit are available, as is an acceptable
2-generation reproduction study in the rat.  The HIARC concluded that a
developmental neurotoxicity study with glyphosate is not required due to
the absence of neurotoxicity in any study. 

Based on the available data, there was no evidence of quantitative or
qualitative increased susceptibility following in utero glyphosate
exposure to rats and rabbits, or  following pre/post natal exposure in
the 2-generation reproduction study in rats.

The FQPA SFC concluded that the safety factor of 10x be removed (reduced
to 1x) because

	1)  There is no evidence of quantitative or qualitative increased
susceptibility of the young demonstrated in the prenatal developmental
studies in rats and rabbits and pre/post natal reproduction study in
rats;

	2)  The toxicology data base is complete;

	3)  A developmental neurotoxicity study is not required; and

	4)  The dietary (food and drinking water) exposure assessments will not
underestimate the potential exposures for infants and children.

4.6	Endocrine disruption  TC \l2 "4.6	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).

Potential estrogen, androgen, and/or thyroid mediated toxicity was not
indicated in any test for glyphosate.

5.0	Public Health Data  TC \l1 "5.0	Public Health Data 

5.1	Incident Reports  TC \l2 "5.1	Incident Reports 

Information from a coca eradication program in Columbia was examined to
determine the potential for adverse health effects from possible
exposure to residues of glyphosate.  None of the data from the Columbian
reports provide a compelling evidence of a causal relationship between
exposure to glyphosate and incidence of illness reported in the study.  
 

6.0  Exposure Characterization/Assessment  TC \l1 "6.0  Exposure
Characterization/Assessment 

6.1	Dietary Exposure/Risk Pathway  TC \l2 "6.1	Dietary Exposure/Risk
Pathway 

6.1.1	Residue Profile  TC \l3 "6.1.1	Residue Profile 

6.1.1.1  Residues in Food

The qualitative nature of the residue in plants is adequately
understood.  Studies with a variety of plants including corn, cotton,
soybeans, and wheat indicate that the uptake of glyphosate or its
metabolite, AMPA, from soil is limited and is readily translocated. 
Metabolism via N-methylation yields N-methylated glycines and phosphonic
acids.  In an 8/19/92 meeting, the HED Metabolism Committee determined
that, based on toxicological considerations, AMPA need not be regulated
and should be dropped from the tolerance expression (Memo, R. Perfetti,
10/19/92).  Furthermore, the Committee determined that, based on
toxicological considerations, AMPA need not be regulated regardless of
levels observed in foods or feeds (Memo, R. Perfetti, 3/17/94).

The qualitative nature of glyphosate residues in livestock is adequately
understood.  Studies with lactating goats and laying hens fed a mixture
of glyphosate and AMPA indicate that the primary route of elimination
was by excretion (urine and feces).  These results are consistent with
metabolism studies in rats, rabbits, and cows.  The terminal residues in
eggs, milk, and livestock tissues are glyphosate and its metabolite
AMPA.  The conclusions of the HED Metabolism Committee on 10/19/92 and
3/17/94 apply to plant and livestock commodities.  Thus, the terminal
residue to be regulated in livestock is glyphosate per se, and
glyphosate is the only compound for which a risk assessment is required.

Adequate enforcement methods are available for analysis of residues of
glyphosate in or on plant and livestock commodities.  These methods
include Gas Liquid Chromatography (GLC) (Method I in Pesticides
Analytical Manual (PAM) II; the LOD is 0.05 ppm) and HPLC with
fluorometric detection.  These analytical methods are adequate for
residue data collection and enforcement of the proposed tolerances of
glyphosate in/on Indian mulberry and dry peas.  Data from the Pestrak
database (1990 and 2005) indicate that recoveries are not likely for
glyphosate under FDA Multiresidue Methods.  No further data regarding
multiresidue methods are required for this proposed use. 

IR-4 has submitted field trial data for glyphosate on dry pea.  In all
trials, Roundup Ultra® Herbicide was applied to preemergence plants,
with a second foliar application to the physiologically mature crop;
registration is being sought for Roundup WeatherMax®.  The only
difference between the test substance (Roundup Ultra® Herbicide) and
the proposed registered product (Roundup WeatherMax®) is the percent
active ingredient in the formulated product.  

At four of the trial sites (WA sites and 1 ND site), two applications of
the 3 lb ae/gal (4 lb a.i./gal) IPA formulation were made as a preplant
soil application 3 days prior to planting and as a broadcast foliar
application to mature peas 7 days prior to harvest, with a 91-day
retreatment interval.  A new trial was begun at the fifth trial site
because plants were lost due to powdery mildew, and plants at this site
received only the harvest aid application.  Application rates were
2.16-2.27 lb ae/A (2.88-3.02 lb a.i./A) for preplant applications (~0.6x
the maximum established preplant/preemergence application rate) and
2.21-2.35 lb ae/A (2.95-3.13 lb a.i./A) for harvest aid applications
(~1x the maximum proposed application rate).  Therefore, total
application rates at sites receiving both applications were 4.42-4.51 lb
ae/A (5.89-6.01 lb a.i./A) (~0.75x the maximum established seasonal
application rate).  The application rate at the site receiving only the
harvest aid application was 2.21 lb ae/A (2.95 lb a.i./A).  A nonionic
surfactant was added to the spray mixture for all applications.  

Because glyphosate adsorbs strongly to the soil, the preplant
application is expected to result in negligible residues; therefore,
ARIA concludes that the trial in which no preplant application was made
may be considered representative of the requested use.  Although the
total application rates used in the trials reflect only 0.75x the
maximum established seasonal rate to dry pea, the use patterns of the
submitted trials reflect the proposed use, which is a higher harvest aid
application rate with a lower PHI.   

Samples of dry pea were analyzed for residues of glyphosate using an
HPLC/FLD method.  The validated LOQ was 0.05 ppm, and the LOD was 0.025
ppm.  This method is adequate for data collection based on acceptable
method validation and concurrent recovery data.  The results from the
dry pea field trials show that residues in dry pea harvested 7 days
following preplant + harvest aid application at a total seasonal rate of
4.42-4.51 lb ae/A (5.89-6.01 lb a.i./A) were 0.59-3.57 ppm.  Residues in
two samples of dry pea harvested 7 days following a single harvest aid
application at 2.21 lb ae/A (2.95 lb a.i./A) were 2.20 and 6.19 ppm. 
ARIA notes that residues in samples from the ND trial sites greatly
exceeded residues in samples from the WA sites.  Residues ranged
0.66-0.81 ppm in samples from the WA sites, while residues at the ND
sites ranged 2.20-6.19 ppm.  Although the petitioner noted some unusual
weather conditions at the ND sites, weather conditions were not reported
to affect plant growth and development.

The MRL Spreadsheet was used to estimate recommended glyphosate
tolerances in pea, dry.  The petitioner proposed a tolerance of 8.0 ppm
for Vegetable, Legume, Group 6, except soybean.  The spreadsheet
confirms the tolerance value of 8.0 ppm based upon the data set from the
residue field trials; however, the data only support a tolerance of 8.0
ppm on pea, dry.  Therefore, ARIA recommended for the requested
glyphosate tolerance of 8.0 ppm on pea, dry, not the entire Vegetable
Legume, Group 6, except soybean.

The dietary risk assessment used tolerance values as listed in 40 CFR §
180.364, in addition to the proposed tolerances of 0.20 ppm on Indian
mulberry and 8.0 ppm for pea, dry (including chickpeas and lentils).

6.1.1.2  Residues in Water

Based on the GENEEC and SCI-GROW models, the EECs of glyphosate for
acute exposures are estimated to be 21 parts per billion (ppb) for
surface water and 0.0038 ppb for ground water.  The EECs for chronic
exposures are estimated to be 0.83 ppb for surface water and 0.0038 ppb
for ground water, based on glyphosate treatment in crops.  To estimate
the possible concentration of glyphosate in surface water resulting from
direct application to water, the Agency assumed application to a water
body 6 feet deep.  At an application rate of 3.75 lb acid equivalent
(ae)/A, the estimated concentration is 230 ppb.  Because the glyphosate
water-application estimate is greater than the crop application
estimate, a value of 230 ppb was used in estimating chronic exposures
and risk.

6.1.2	Acute and Chronic Dietary Exposure and Risk  TC \l3 "6.1.2	Acute
and Chronic Dietary Exposure and Risk 

No toxicological endpoint attributable to a single dose of glyphosate
was identified by HED’s former HIARC.  The risk assessment team agrees
with this conclusion; therefore, an acute dietary exposure assessment
was not conducted.

™, Version 2.03, which uses food consumption data from the USDA’s
Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996
and 1998.  The analysis was performed to support the Section 3 request
for the registration and use of glyphosate on Indian mulberry for weed
control and on pea, dry for weed control and as a harvest aid. 

The Tier 1 chronic dietary analysis for glyphosate is a conservative
estimate of dietary exposure that used tolerance level residues and 100%
crop treated.  The risk estimate from chronic dietary exposure estimates
for food and drinking water to glyphosate as represented by the %PAD is
below EPA’s level of concern for the U.S. population and all
population subgroups.  The exposure estimate of the U.S. population is
2% of the cPAD.  The exposure estimate for the most highly exposed
subpopulation (All infants <1 year old)) is 7% of the cPAD.  Glyphosate
is classified as a not likely human carcinogen, so a cancer dietary
exposure analysis is not required.

As discussed in section 6.1.1.2, a value of 230 ppb was used directly in
the DEEM chronic dietary exposure and risk assessment.

Table 6.1.2	Summary of Dietary Exposure and Risk for Glyphosate.

Population Subgroup a	Acute Dietary

Not Required	Chronic Dietary	Cancer Dietary

Not Required

	aPAD, mg/kg	Exposure,  mg/kg/day 	% aPAD	cPAD,  mg/kg/day	 Exposure, 

mg/kg/day	% cPAD	Exposure mg/kg/day	Risk

General U.S. Population	Not Applicable	1.75	0.040979	2	Not Applicable

All Infants (< 1 yr)

	0.127562	7

	Children 1-2 yrs

	0.094755	5

	Children 3-5 yrs

	0.087797	5

	Children 6-12 yrs

	0.059417	3

	Youth 13-19 yrs

	0.036601	2

	Adults 20-49 yrs

	0.033410	2

	Adults 50+ yrs

	0.028329	2

	Females 13-49 yrs

	0.030628	2

	a The value for the population with the highest risk is shown in
boldface.

6.2	Water Exposure/Risk Pathway  TC \l2 "6.2	Water Exposure/Risk Pathway

The Agency estimated the concentration in surface water resulting from
direct application to a water body 6 feet deep. This estimate is based
on a dilution model that does not take into account degradation in the
water body and partitioning into the water column-sediment phases. The
estimate considered a single broadcast application at the maximum
application rate of 3.75 lb of glyphosate free acid per acre.  Based on
a maximum total application rate of 3.75 pounds of glyphosate free acid
per acre, the estimated concentration for use in the drinking water
assessment is 230 (g/L (ppb).

The general approach to estimate concentrations in surface water used as
drinking water sources is to assume exposure from runoff and spray
drift, whereas the approach for estimating concentrations of drinking
water from surface water sources and ecological risks to aquatic
organisms from use of herbicides at aquatic sites is to assume direct
application of product to water.  Direct application to surface water
assumes that all of the product enters the water body instantaneously
and is uniformly mixed throughout the water column, whereas with runoff
and spray drift only some fraction of the product that is applied is
assumed to enter the water body.  The maximum application rate in any
single broadcast application to aquatic sites is not to exceed 3.75
pounds of “glyphosate free acid” per acre.  Given the higher mass of
pesticide in surface water that results from direct application relative
to runoff and drift, estimates of concentrations in surface water based
on direct application to water at maximum single broadcast application
rates for aquatic sites represent worst case estimates and are higher
than estimates based on exposures from runoff and drift.

6.3	Residential (Non-Occupational) Exposure/Risk Pathway  TC \l2 "6.3
Residential (Non-Occupational) Exposure/Risk Pathway 

6.3.1	Home Uses  TC \l3 "6.3.1	Home Uses 

Glyphosate, isopropylamine salt is registered for broadcast and spot
treatments on home lawns and gardens by homeowners and by lawn care
operators (LCOs).  Based on the registered residential use patterns,
there is a potential for short-term dermal and inhalation exposures to
homeowners who apply products containing glyphosate (residential
handlers).  Additionally, based on the results of environmental fate
studies, there is also a potential for short- and intermediate-term
post-application dermal exposures by adults and toddlers and incidental
ingestion exposures by toddlers.  However, since HIARC did not select
short- or intermediate-term dermal or inhalation endpoints, no
residential handler or post-application dermal assessment is required;
only a post-application toddler assessment for incidental ingestion
exposures is included.  Risk estimates for toddler post-application
incidental ingestion exposures ranged from 7,230 to greater than 106. 
All recreational and residential exposures assessed do not exceed the
Agency’s level of concern (MOEs <100).

Glyphosate, isopropylamine salt is registered for broadcast and spot
treatments on home lawns and gardens.  Glyphosate products for homeowner
use are packaged as ready-to-mix formulations and ready-to-use sprayers
and are very common in home and garden stores in the U.S.  Glyphosate
products are also used by LCOs for broadcast and spot treatment weed
control programs on homeowner lawns.  Glyphosate products are also
labeled for turf renovation.  The following products are registered for
residential lawn use, including lawn renovation (anticipated to
represent the worst-case residential exposure):

Roundup ProTM (EPA Reg No. 524-475): soluble concentrate containing 41%
glyphosate, maximum application rate = 1.5 lb ae/A

Roundup ProDryTM (EPA Reg No. 524-505):   formulation containing 71.4%
glyphosate, maximum application rate = 1.62 lb ae/A

To characterize the persistence of glyphosate in the environment for
this assessment, studies referenced in the Glyphosate RED, reported that
half-lives in field studies (including soils) conducted in the coldest
climates (i.e., Minnesota, New York and Iowa) were the longest and
ranged from about 29 days up to about 140 days, indicating that
glyphosate residues in the field are somewhat more persistent in cooler
climates as opposed to milder ones (Georgia, California, Arizona, Ohio,
and Texas).  Also, glyphosate was shown to remain predominantly in the
0-6 inch soil layer at all field sites in one study.

Based on the registered residential use patterns, there is a potential
for short-term dermal and inhalation exposures to homeowners who apply
products containing glyphosate (residential handlers).  Additionally,
based on the results of environmental fate studies, there is a potential
for short- and intermediate-term post-application dermal exposures by
adults and toddlers and incidental ingestion exposures by toddlers. 
However, since HIARC did not select short- or intermediate-term dermal
or inhalation endpoints, no residential handler or post-application
dermal assessment is included; only a post-application toddler
assessment for incidental ingestion exposures is presented below.

The SOPs For Residential Exposure Assessments, Draft (12/17/97) and
Exposure Science Advisory Committee (ExpoSAC) Policy No. 11, (2/22/01): 
Recommended Revisions to the SOPs for Residential Exposure was used to
estimate post-application incidental ingestion exposures and risk
estimates for toddlers.   The following assumptions were used to assess
exposures to toddlers after contact with treated lawns: 

toddler body weight: 15 kg.

toddler hand surface area is 20 cm2, and a toddler performs 20
hand-to-mouth events per hour for short-term exposures. 

exposure duration: 2 hours per day.	

5% of application rate represents fraction of glyphosate available for
transfer to hands and a 50% saliva extraction factor for hand-to-mouth
exposures. 

surface area of a object (for toddler object-to-mouth exposures) is
approximately 25 cm2.  

20% of application rate available as dislodgeable residues for
object-to-mouth exposures.

100% of application rate is available in the top 1 cm of soil for soil
ingestion exposures.  Also, it is assumed that a toddler can ingest 100
mg soil/d.

Table 6.3.1 provides a summary of the short- and intermediate-term risk
estimates for 

post-application incidental ingestion exposures to toddlers.



Table 6.3.1: Summary of Toddler Incidental Ingestion Exposures and Risk
Estimates 

for Residential Use of Glyphosate, Isopropylamine salt1

Activity	AR (lbs a.e./A)2	Residue Estimate3	PDR

(mg/kg bw/d)4	Short-/Intermediate-term MOE5

Hand-to-mouth	1.62	DFR:  0.908 Fg/cm2	0.0242 	7,230

Object-to-mouth

DFR: 3.63 Fg/cm2	0.00605	28,900

Soil Ingestion

Soil residue:  12.2 Fg/g soil	8.13 x 10-5	> 106

Notes:

 1.  Sources: Standard Operating Procedures for Residential Exposure
Assessments, Draft, December 17, 1997 and Exposure SAC Policy No. 11,
Feb. 22, 2001: Recommended Revisions to the SOPs for Residential
Exposure.

2.  AR = maximum application rate on Roundup ProDry label (EPA Reg. No.
524-505) for residential lawn treatment.

3.  Residue estimates based on the following protocol from the
Residential SOPs:

 	a.  Hand-to-mouth DFR = 1.62 lb ae/A x 0.05 x (4.54 x 108 Fg/lb ae) x
( 2.47 x 10-8 A/cm2) = 0.908 Fg/cm2.

b.  Object-to-mouth DFR = 1.62 lb ae/A x 0.20 x (4.54 x 108 Fg/lb ae) x
( 2.47 x 10-8 A/cm2) = 3.63 Fg/cm2.

c.  Soil Residue = 1.62 lb ae/A x fraction of residue in soil (100%)/cm 
x  (4.54 x 108 Fg/lb ae) x ( 2.47 x 10-8 A/cm2) x 0.67 cm3/g= 12.2 Fg/g
soil.

4.  Potential Dose Rate (PDR; already normalized to body weight of
toddler)

a.  Hand-to-mouth PDR = (0.908 Fg/cm2 x 0.50 x 20 cm2/event x 20
events/hr x 10-3 mg/Fg x 2 hrs/d)/15 kg = 0.0242 mg/kg bw/d .

b.  Object-to-mouth PDR = (3.63 Fg/cm2 x  25 cm2/d x 10-3 mg/Fg)/15 kg =

0.00605 mg/kg bw/d

c.  Soil Ingestion PDR = (12.2 Fg/g soil x 100 mg soil/d x 10-6 g/Fg)/15
kg = 

8.13 x 10-5 mg/kg bw/d 

5.  MOE = NOAEL/PDR, where the short-term incidental oral NOAEL = 175
mg/kg/d the Agency’s level of concern is for MOEs < 100 (short-term
residential).			

All MOEs calculated for post-application toddler exposures do not exceed
the Agency’s level of concern for residential exposures (MOEs < 100).

6.3.2	Recreational Uses  TC \l3 "6.3.2	Recreational Uses 

Glyphosate, isopropylamine salt is registered for use in recreational
areas, including parks and golf courses for control of broadleaf weeds
and grasses.  It is also registered for use in lakes and ponds,
including reservoirs, for control of nuisance aquatic weeds.  Based on
the registered uses, adult and child golfers are anticipated to have
short-term post-application dermal exposure at golf courses.  Swimmers
(adults, children and toddlers) are anticipated to have short-term
post-application dermal and incidental ingestion exposures.  However,
since HIARC did not select dermal endpoints, no post-application dermal
assessment is included; only a post-application incidental ingestion
exposure assessment (swimmers) is required.  Risk estimates for
incidental ingestion by swimmers (adults, children and toddlers) ranged
from 7,610 to 35,500.

Table 6.3.2.  Assumptions and Risk Estimates for Post-Application
Swimmer 

Exposure Assessments for Glyphosate, Isopropylamine salt

Exposure Scenario

	

AR1

(lb a.e./A)	

Maximum Concentration in water (mg/L)2	

Potential Dose Rate (PDR; oral mg/kg bw/day) 3 	

Short-term MOE4

Incidental Oral Ingestion, Adult-female	

3.75	

1.38	

0.00493	

35,500

Incidental Oral, toddler

	

0.023	

7,610

Notes

1.  Application rate from registered labels for aquatic weed control
using glyphosate IPA salt (ex. label = EPA Reg. No. 524-343; max rate =
7.5 pints/A containing 4 lb acid equivalent [ae] glyphosate/gal. x 1
gal./4 pints = 3.75 lb ae/A.

2.  Maximum concentration in water (top 1 ft.) = 3.75 lb ae/A x
1A/43,560 ft2 x 454,000 mg/lb x 1/ft x ft3/28.32 L = 1.38 mg/L.

3.  PDR, incidental oral exposure = concentration, Cw (mg/L) x ingestion
rate, IgR (L/hr) x exposure time, ET (hrs/d) x 1/BW (adult-female=60 kg;
toddler = 15 kg)

4.  MOE = NOAEL/PDR; short-term incidental oral NOAEL = 175 mg/kg bw/d; 
The level of concern for adult females and toddlers for short-term,
incidental oral exposures is MOEs < 100.

The MOEs presented in Table 6.3.2 for post-application exposure by
swimmers to glyphosate in aquatic weed control applications are greater
than 100 and do not exceed the Agency’s level of concern for
short-term non-occupational (recreational) exposures (MOEs < 100).

6.3.3	Other (Spray Drift, etc.)  TC \l3 "6.3.3	Other (Spray Drift, etc.)

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 the ground application method employed for glyphosate. 
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.  On
a chemical by chemical basis, 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 with specific products with significant risks
associated with drift.

7.0	Aggregate Risk Assessments and Risk Characterization  TC \l1 "7.0
Aggregate Risk Assessments and Risk Characterization 

7.1	Acute Aggregate Risk  TC \l2 "7.1	Acute Aggregate Risk 

The Agency did not conduct an acute aggregate risk analysis because the
HIARC did not identify an acute dietary dose/endpoint (TXR No. 0050428,
W. Dykstra, 1/22/02).

7.2	Short-and Intermediate-Term Aggregate Risk  TC \l2 "7.2	Short-and
Intermediate-Term Aggregate Risk 

In aggregating short- and intermediate-term risk, the Agency considered
background chronic dietary exposure (food + water) and short- and
intermediate-term incidental oral exposures (see Table 7.2).  Because
the incidental oral ingestion exposure estimates for toddlers from
residential turf exposures (Table 6.3.1) exceeded the incidental oral
exposure estimates from post-application swimmer exposures (Table
6.3.2), the Agency conducted this risk assessment using exposure
estimates from just the worst-case situation.  No attempt was made to
combine exposures from the swimmer and residential turf scenarios due to
the low probability of both occurring.   

The total short- and intermediate-term food and residential aggregate
MOEs are 1400 to 4610.  As these MOEs are greater than 100, the short-
and intermediate-term aggregate risk does not exceed the Agency’s
level of concern.  The EEC resulting from the registered use of direct
glyphosate application to surface water is 230 ppb, and this value was
utilized as an EDWC and used as the water residue directly in the DEEM
dietary exposure risk assessment.  Dietary (food + water) exposure can
be added to the estimated residential exposure because the oral and
dermal endpoints are the same.  The combined exposure may then be used
to calculate an MOE for aggregate risk.  Doing so results in an
aggregate MOE of 1400 for the most highly-exposed population subgroup,
children 1-2 years old.  Therefore, ARIA concludes with reasonable
certainty that residues of glyphosate in drinking water do not
contribute significantly to the short/intermediate-term aggregate human
health risk at the present time.  Table 7.2 summarizes the
short/intermediate-term aggregate exposure to glyphosate residues.

Table 7.2.	Short-Term and/or Intermediate-Term Aggregate Risk

Population	Short or Intermediate-Term Scenario

	NOAEL

mg/kg/day	Target

MOE1	Max

Exposure2

mg/kg/day	Average

Food + Water

Exposure

mg/kg/day	Residential Exposure3

mg/kg/day	Aggregate MOE

(food and

residential)4

Children 1-2	175	100	1.75	0.095	0.030	1400

Adults 20-49 yrs	175	100	1.75	0.033	0.0049	4610

1 The target MOE is based only on the inter- and intra- species safety
factors totaling 100.

2 Maximum Exposure (mg/kg/day) = NOAEL/Target MOE

3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation
Exposure]

4 Aggregate MOE = [NOAEL/(Avg Food Exposure + Residential Exposure)]

7.3	Intermediate-Term Aggregate Risk  TC \l2 "7.3	Intermediate-Term
Aggregate Risk 

See discussion and summary Table 7.2 in Section 7.2.

7.4	Long-Term Aggregate Risk  TC \l2 "7.4	Long-Term Aggregate Risk 

Long-term chronic risk does not include estimates of residential risk. 
Furthermore, water residues were incorporated into the chronic dietary
risk assessment, so in effect, the chronic dietary risk assessment also
provides the estimate of long-term aggregate risk.  Long-term aggregate
risk does not exceed the Agency’s level of concern.

7.5	Cancer Risk  TC \l2 "7.5	Cancer Risk 

There is no evidence of carcinogenicity in any glyphosate toxicity
study, and it has been classified as negative for carcinogenicity in
humans.  Therefore, a cancer risk assessment was not conducted.

8.0	Cumulative Risk Characterization/Assessment  TC \l1 "8.0	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 [chemical name] and any other
substances and glyphosate does not appear to produce a toxic metabolite
produced by other substances. For the purposes of this tolerance action,
therefore, EPA has not assumed that glyphosate has 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
http://www.epa.gov/pesticides/cumulative/.

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

9.1	Short/Intermediate/Long-Term Handler Risk  TC \l2 "9.1
Short/Intermediate/Long-Term Handler Risk 

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socks, and chemical-resistant gloves.  If the application solution is
30% or less of the product, applicators must wear PPE consisting of a
long-sleeved shirt, long pants, and shoes with socks.

9.2	Short/Intermediate/Long-Term Postapplication Risk  TC \l2 "9.2
Short/Intermediate/Long-Term Postapplication Risk 

A handler or occupational post-application assessment was not required
because no short-term dermal or inhalation endpoints were selected by
HIARC.  However, the recommendation to increase the REI from 4 to 12
hours (DP Num: 830831, W. H. Donovan, W.G. Dykstra, and J. T.
Swackhammer, 2/20/02) has not been implemented.

10.0	Data Needs and Label Requirements  TC \l1 "10.0	Data Needs and
Label Requirements 

10.1	Toxicology  TC \l2 "10.1	Toxicology 

None.

10.2	Residue Chemistry  TC \l2 "10.2	Residue Chemistry 

None

10.3	Occupational and Residential Exposure  TC \l2 "10.3	Occupational
and Residential Exposure 

A previous risk assessment (DP Num: 830831, W. H. Donovan, W. G.
Dykstra, and J. T. Swackhammer, 2/20/02) required that the REI should be
increased from 4 to 12 hours.  Unless a suitable rebuttal has been
approved by the Agency, this requirement remains outstanding.

References  TC \l1 "References 

DP Num: 280831, W. H. Donovan, W. G. Dykstra
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