Document ID: EPA-HQ-OPP-2006-0177-0006
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: 9/5/06

MEMORANDUM

SUBJECT:	Glyphosate Human Health Risk Assessment for Proposed Uses on
Safflower and Sunflower. PC Code: 103601, Petition No: 4E6878, DP Num:
314476.

		Regulatory Action: Section 3 Registration Action

		Risk Assessment Type: Single Chemical Aggregate

							

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

		Fungicide Branch

		Registration Division (7505P)

THROUGH:	P.V. Shah, PhD., Branch Senior Scientist

		Registration Action Branch 1

		Health Effects Division (7509P)

			AND

		W. Cutchin, Acting 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
_Toc140401595 \h  4 

2.0	Ingredient Profile	  PAGEREF _Toc140401596 \h  6 

2.3	Physical and Chemical Properties	  PAGEREF _Toc140401597 \h  8 

3.0	Metabolism Assessment	  PAGEREF _Toc140401598 \h  8 

3.1 	Comparative Metabolic Profile	  PAGEREF _Toc140401599 \h  8 

3.2	Nature of the Residue in Foods	  PAGEREF _Toc140401600 \h  9 

3.2.1.	Description of Primary Crop Metabolism	  PAGEREF _Toc140401601 \h
 9 

3.2.2	Description of Livestock Metabolism	  PAGEREF _Toc140401602 \h  9 

3.2.3	Description of Rotational Crop Metabolism	  PAGEREF _Toc140401603
\h  9 

3.3 	Environmental Degradation	  PAGEREF _Toc140401604 \h  10 

3.4	Toxicity Profile of Major Metabolites and Degradates	  PAGEREF
_Toc140401605 \h  10 

3.5	Summary of Residues for Tolerance Expression and Risk Assessment	 
PAGEREF _Toc140401606 \h  10 

3.5.1	Tabular Summary	  PAGEREF _Toc140401607 \h  10 

4.0  Hazard Characterization/Assessment	  PAGEREF _Toc140401608 \h  11 

4.1	Hazard Characterization	  PAGEREF _Toc140401609 \h  11 

4.2	FQPA Hazard Considerations	  PAGEREF _Toc140401610 \h  14 

4.2.1	Adequacy of the Toxicity Data Base	  PAGEREF _Toc140401611 \h  14 

4.2.2	Evidence of Neurotoxicity	  PAGEREF _Toc140401612 \h  14 

4.2.3	Developmental Toxicity Studies	  PAGEREF _Toc140401613 \h  14 

4.2.4	Reproductive Toxicity Study	  PAGEREF _Toc140401614 \h  15 

4.2.6  Pre-and/or Postnatal Toxicity	  PAGEREF _Toc140401615 \h  15 

4.2.6.1  Determination of Susceptibility	  PAGEREF _Toc140401616 \h  15 

4.2.6.2  Degree of Concern Analysis and Residual Uncertainties for Pre
and/or Post-natal Susceptibility	  PAGEREF _Toc140401617 \h  15 

4.3	Recommendation for a Developmental Neurotoxicity Study	  PAGEREF
_Toc140401618 \h  15 

4.3.1	Evidence that supports requiring a Developmental Neurotoxicity
study	  PAGEREF _Toc140401619 \h  16 

4.3.2	Evidence that supports not requiring for a Developmental
Neurotoxicity study	  PAGEREF _Toc140401620 \h  16 

4.4	Hazard Identification and Toxicity Endpoint Selection	  PAGEREF
_Toc140401621 \h  16 

4.4.1   Acute Reference Dose (aRfD) - Females age 13-49	  PAGEREF
_Toc140401622 \h  16 

4.4.2	Acute Reference Dose (aRfD) - General Population	  PAGEREF
_Toc140401623 \h  16 

4.4.3	Chronic Reference Dose (cRfD)	  PAGEREF _Toc140401624 \h  16 

4.4.4	Incidental Oral Exposure (Short and Intermediate Term)	  PAGEREF
_Toc140401625 \h  17 

4.4.5	Dermal Absorption	  PAGEREF _Toc140401626 \h  17 

4.4.6	Dermal Exposure (Short, Intermediate and Long Term)	  PAGEREF
_Toc140401627 \h  17 

4.4.7	Inhalation Exposure (Short, Intermediate and Long Term)	  PAGEREF
_Toc140401628 \h  17 

4.4.8	Margins of Exposure and Levels of Concern	  PAGEREF _Toc140401629
\h  17 

4.4.9	Recommendation for Aggregate Exposure Risk Assessments	  PAGEREF
_Toc140401630 \h  17 

4.4.10	Classification of Carcinogenic Potential	  PAGEREF _Toc140401631
\h  17 

4.5	Special FQPA Safety Factor	  PAGEREF _Toc140401632 \h  19 

4.6	Endocrine disruption	  PAGEREF _Toc140401633 \h  20 

5.0	Public Health Data	  PAGEREF _Toc140401634 \h  20 

5.1	Incident Reports	  PAGEREF _Toc140401635 \h  20 

6.0  Exposure Characterization/Assessment	  PAGEREF _Toc140401636 \h  21

6.1	Dietary Exposure/Risk Pathway	  PAGEREF _Toc140401637 \h  21 

6.1.1	Residue Profile	  PAGEREF _Toc140401638 \h  21 

6.1.2	Acute and Chronic Dietary Exposure and Risk	  PAGEREF
_Toc140401639 \h  22 

6.2	Water Exposure/Risk Pathway	  PAGEREF _Toc140401640 \h  24 

6.3	Residential (Non-Occupational) Exposure/Risk Pathway	  PAGEREF
_Toc140401641 \h  24 

6.3.1	Home Uses	  PAGEREF _Toc140401642 \h  24 

6.3.2	Recreational Uses	  PAGEREF _Toc140401643 \h  27 

6.3.3	Other (Spray Drift, etc.)	  PAGEREF _Toc140401644 \h  27 

7.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF
_Toc140401645 \h  28 

7.1	Acute Aggregate Risk	  PAGEREF _Toc140401646 \h  28 

7.2	Short-and Intermediate-Term Aggregate Risk	  PAGEREF _Toc140401647
\h  28 

7.3	Intermediate-Term Aggregate Risk	  PAGEREF _Toc140401648 \h  29 

7.4	Long-Term Aggregate Risk	  PAGEREF _Toc140401649 \h  29 

7.5	Cancer Risk	  PAGEREF _Toc140401650 \h  29 

8.0	Cumulative Risk Characterization/Assessment	  PAGEREF _Toc140401651
\h  29 

9.0	Occupational Exposure/Risk Pathway	  PAGEREF _Toc140401652 \h  30 

9.1	Short/Intermediate/Long-Term Handler Risk	  PAGEREF _Toc140401653 \h
 30 

9.2	Short/Intermediate/Long-Term Postapplication Risk	  PAGEREF
_Toc140401654 \h  30 

10.0	Data Needs and Label Requirements	  PAGEREF _Toc140401655 \h  30 

10.1	Toxicology	  PAGEREF _Toc140401656 \h  30 

10.2	Residue Chemistry	  PAGEREF _Toc140401657 \h  30 

10.3	Occupational and Residential Exposure	  PAGEREF _Toc140401658 \h 
31 

 

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 safflower and
sunflower.

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 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 LOAEL of 350 mg/kg/day is based on maternal
toxicity.  A 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 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, aminomethylphosphonic acid (AMPA) need
not be regulated regardless of levels observed in foods or feeds. 
Consequently, the terminal residue to be regulated in plants and animals
is glyphosate per se.

The IR-4 submitted field trial data for glyphosate
(N-(phosphonomethyl)glycine) on safflower and sunflower.  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®.  A total of 6.0
lb a.i./A (6.7 kg a.i./hectare) of compound was applied per season in
the safflower trials, approximately 109% of the proposed label rate for
WeatherMAX®.  The treatment interval was 106 days in all safflower
trials.  The number and locations of safflower field trials are not in
accordance with OPPTS Guideline 860.1500.  Based on the available data,
TRB extended the sunflower data to cover safflower even though it has a
higher use rate.  In each sunflower trial, Roundup Ultra® Herbicide was
to be applied to preemergent sunflowers, with a second foliar
application to the physiologically mature crop.  A total of 2.0 lb
a.i./A (2.24 kg a.i./hectare) of compound was to be applied per treated
plot, approximately 105% of the proposed label rate.  The interval
between treatments ranged from 105 to 118 days.  The number and
locations of sunflower field trials are not in accordance with OPPTS
Guideline 860.1500 because no trials were conducted in Region 8 as
required by the Guidelines.  However, the two trials conducted in
Scottsbluff, NE were 60 miles from Region 8 and this deviation from
Guideline requirements is insignificant.

Glyphosate residues were quantitated in sample extracts of safflower and
sunflower RACs and processed commodities using an approved method, a
two-column-switching HPLC equipped with an o-phthalaldehyde post-column
reactor and a fluorescence detector.  Safflower seed was harvested at a
7-day PHI.  The results from these trials show that glyphosate residues
ranged from 1.1 ppm to 2.9 ppm on/in treated safflower seed when the
test substance was applied at the seasonal application rate of
approximately 6 lb a.i./A.  Sunflower seed was harvested at a 6 to 8-day
PHI.  The proposed PHI is 7 days, and these deviations are considered
insignificant.  The results from these trials show that glyphosate
residues ranged from 0.07 to 20 ppm on/in treated sunflower seed when
the test substance was applied at a seasonal application rate of 1.32 to
2.54 lb a.i./A with a 6 to 8-day PHI.

The MRL Spreadsheet (PMRA PRO2005-04, 9/28/05) was used to estimate
recommended glyphosate tolerances in safflower and sunflower.  The
petitioner proposed a tolerance of 25 ppm for safflower and sunflower. 
The spreadsheet indicates a much higher recommended tolerance than that
being proposed.  Therefore, TRB recommended for the requested glyphosate
tolerance of 85 ppm on safflower and sunflower.

For crop applications, the acute and chronic estimated environmental
concentration (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, and was used as a Drinking Water Estimated Concentration (DWEC). 

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 PAD (cPAD).  The exposure
estimate for the most highly exposed subpopulation (Non-nursing infants
<1 year old)) is 9% of the cPAD.   

Margins of Exposure (MOEs) ranged from 930 (non-nursing infants < one
year) to 2800 (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.

The petitioner should submit a revised supplemental label for the
proposed uses on safflower and sunflower including a 30-day plant back
restriction for rotational crops.  Pending submission of a revised
supplemental label and the results of the forthcoming human health risk
assessment, TRB recommends for the establishment of tolerances for the
residues of glyphosate on/in safflower and sunflower at 85.0 ppm.

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

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

The IR-4 has submitted field trial data for glyphosate
(N-(phosphonomethyl)glycine) on safflower and sunflower.  The proposed
use patterns are summarized in Table 2.1.

Table 2.1.	Summary of Directions for Use of [Chemical].

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

Safflower

Treatment 1

Preplant, preemergence, at-planting	524-537	Up to 2.75	1	2.75 Treatments

1 and 2 combined	Not

specified	See maximum seasonal rate

Treatment 2

In established crop: hooded or shielded sprayers in row middles, wiper
applications in row middles 	524-537	Up to 2.75	Not specified	2.75

Treatments 

1 and 2 combined	Not

specified	See maximum seasonal rate

Treatment 3

Preharvest	524-537	Up to 2.75	Not specified, more than 1 is unlikely
2.75	7	Apply to physiologically mature crop when seed has lost its
opaqueness, 20 to 30 days after the end of flowering of the secondary
branches

Post-harvest		524-537	According to "Weeds Tables" of the basic
WeatherMAX® label	Not specified

	Sunflower

Treatment 1

Preplant, preemergence, at-planting	524-537	Up to 0.95	1	0.95

(1.06)

Treatments 

1 and 2 combined	Not

specified	See maximum seasonal rate

Treatment 2

In established crop: hooded or shielded sprayers in row middles, wiper
applications in row middles	524-537	Up to 0.95	Not specified	0.95

(1.06)

Treatments 

1 and 2 combined	Not

specified	See maximum seasonal rate

Treatment 3

Preharvest	524-537	Up to 0.95	Not specified, more than 1 is unlikely
0.95	7	Apply to physiologically mature crop when the backsides of
sunflower heads are yellow, bracts are turning brown and seed moisture
content < 35%

Post-harvest	524-537	According to "Weeds Tables" of the basic
WeatherMAX® label

Not specified

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 

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

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 aminomethyl phosphonic acid (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 

DP Num: 321667, J. R. Tomerlin, 6/13/06

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,
aminomethylphosphonic acid (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. B. Perfetti, 10/27/92).  In a 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. B. 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. B.
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 estimated environmental
concentration (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  

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

The residue of concern for risk assessment purposes is glyphosate per
se.  The metabolite   Amino-methylphosphonic acid (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 

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

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 aminomethyl phosphonic acid (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 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 (species)	Maternal NOAEL = 175 mg/kg/day

LOAEL = 350 mg/kg/day based on 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

 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). 
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). 

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 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.

 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 incidental oral 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 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 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.

Public Health Data

  TC \l1 "5.0	Public Health Data 

DP Num: 283431, J. Blondell, 6/6/02)

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 effect 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 

DP Num: 321666, J. R. Tomerlin, 6/13/06

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, aminomethylphosphonic acid (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. B. 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. B. 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 GLC (Method I in Pesticides Analytical Manual (PAM) II; the
limit of detection 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 the seed,
meal, and oil of safflower and sunflower, and livestock commodities. 
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. 

The IR-4 submitted field trial data for glyphosate
(N-(phosphonomethyl)glycine) on safflower and sunflower.  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®.  A total of 6.0
lb a.i./A (6.7 kg a.i./hectare) of compound was applied per season in
the safflower trials, approximately 109% of the proposed label rate for
WeatherMAX®.  The treatment interval was 106 days in all safflower
trials.  The number and locations of safflower field trials are not in
accordance with OPPTS Guideline 860.1500.  Based on the available data,
TRB extended the sunflower data to cover safflower even though it has a
higher use rate.  In each sunflower trial, Roundup Ultra® Herbicide was
to be applied to preemergence sunflower, with a second foliar
application to the physiologically mature crop.  A total of 2.0 lb
a.i./A (2.24 kg a.i./hectare) of compound was to be applied per treated
plot, approximately 105% of the proposed label rate.  The interval
between treatments ranged from 105 to 118 days.  The number and
locations of sunflower field trials are not in accordance with OPPTS
Guideline 860.1500 because no trials were conducted in Region 8 as
required by the Guidelines.  However, the two trials conducted in
Scottsbluff, NE were 60 miles from Region 8 and this deviation from
Guideline requirements is considered insignificant.

Glyphosate residues were quantitated in sample extracts of safflower and
sunflower RACs and processed commodities using an approved method, a
two-column-switching HPLC equipped with an o-phthalaldehyde post-column
reactor and a fluorescence detector.  Safflower seed was harvested at a
7-day PHI.  The results from these trials show that glyphosate residues
ranged from 1.1 ppm to 2.9 ppm on/in treated safflower seed when the
test substance was applied at the seasonal application rate of
approximately 6 lb a.i./A.  Sunflower seed was harvested at a 6 to 8-day
PHI.  The proposed PHI is 7 days, and these deviations are considered to
be insignificant.  The results from these trials show that glyphosate
residues ranged from 0.07 to 20 ppm on/in treated sunflower seed when
the test substance was applied at a seasonal application rate of 1.32 to
2.54 lb a.i./A with a 6 to 8-day PHI.

The MRL Spreadsheet (PMRA PRO2005-04, 9/28/05) was used to estimate
recommended glyphosate tolerances in safflower and sunflower.  The
petitioner proposed a tolerance of 25 ppm for safflower and sunflower. 
The spreadsheet indicates a much higher recommended tolerance than that
being proposed.  Therefore, TRB recommended for the requested glyphosate
tolerance of 85 ppm on safflower and sunflower.

The dietary risk assessment used tolerance values as listed in 40 CFR §
180.364, in addition to the proposed tolerances of 85 ppm for all
safflower and sunflower commodities.

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 Hazard Identification Assessment Review
Committee (HIARC); therefore an acute dietary exposure assessment was
not conducted.

A chronic dietary risk assessment was conducted using the Dietary
Exposure Evaluation Model (DEEM-FCID®, 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 safflower 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 chronic PAD (cPAD).  The exposure estimate for the most highly
exposed subpopulation (Non-nursing infants <1 year old)) is 9% of the
cPAD.   Glyphosate is classified as a not likely human carcinogen, so a
cancer dietary exposure analysis is not required.

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.

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	0.040948	2	Not Applicable

All Infants (< 1 yr)

	0.127442	7

	Non-Nursing Infants (< 1 yr)

	0.157626	9

	Children 1-2 yrs

	0.094701	5

	Children 3-5 yrs

	0.087772	5

	Children 6-12 yrs

	0.059403	3

	Youth 13-19 yrs

	0.036570	2

	Adults 20-49 yrs

	0.033380	2

	Adults 50+ yrs

	0.028298	2

	Females 13-49 yrs

	0.030591	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 7,200 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 were 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 	7,200

Object-to-mouth

DFR: 3.63 Fg/cm2	0.00605	29,000

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 7,600 to 36,000.

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	

36,000

Incidental Oral, toddler

	

0.023	

7,600

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 [chemical]. 
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 7.2) 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 930-2800.  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 Estimated Drinking Water Concentration (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 930 for the most
highly-exposed population subgroup, non-nursing infants less than 1 year
old.  Therefore, TRB 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

                              (Option 1: Inhalation/Oral/Dermal
Endpoints and NOAELs the Same)

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

All Infants (<1 yr)	175	100	1.75	0.127	0.030	1113

Non-Nursing Infants (< 1 yr)	175	100	1.75	0.158	0.030	929

Children 1-2	175	100	1.75	0.095	0.030	1400

Children 3-5	175	100	1.75	0.088	0.030	1483

Children 6-12	175	100	1.75	0.059	0.030	1966

Adults 20-49 yrs8	175	100	1.75	0.033	0.030	2778

1 Indicate in this footnote the basis for the target MOE (include the
standard inter- and intra- species safety factors totaling 100, as well
as additional uncertainty factors/safety factors as appropriate.)

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 

See the discussion in Section 6.1.

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 [chemical name] 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 [chemical name]
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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al post-application assessment was required.  The Roundup WeatherMax®
label specifies that for application solutions of 30% or greater
concentration, mixers, loaders, other handlers and applicators must wear
personal protective equipment (PPE) consisting of a long-sleeved shirt,
long pants, shoes with 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. Donvan, 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 

The petitioner should submit a revised supplemental label for the
proposed uses on safflower and sunflower including a 30-day plant back
restriction for rotational crops.

No rotational crop data have been submitted in support of a 0-day
plantback interval (PBI) for rotational crops; therefore, the registrant
should reinstate the 30-day PBI for crops on which use of glyphosate is
not registered (DP Num: 200041, G. Kramer, 5/12/94).  This position was
reiterated in a subsequent review (DP Num: 625970, W. Donovan, 1/31/02).

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.

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