UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D

. C

. 20460

OFFICE OF CHEMICAL SAFETY
AND POLLUTION PREVENTION



### MEMORANDUM

Date: June 4, 2013

SUBJECT: Atrazine, Propazine, and Simazine. Human Health Risk Scoping Document in 

### Support of Regis tration Re view

.

PC Code: 080803

, 080808,080807
Decision No.: 472844 DP Barcode : D407489 Registration No. : NA
Petition No.: NA Regu l atory A ct ion: Registration Review

Case No.: 0062, 0230

, 0070 Risk Assessment Type: Scoping

TXRNo.:NA CAS No. : 1 912-24-9, 139-40-2, 122 -34-9
40 CFR: 180.220

, 180.243, 180.213 MRIDNo. : NA

FROM: William Donovan, PhD, Risk Seyed Tadayon

,**Chemis t~~~~-#**  

### John Liccione

, PhD

, To x icologist
Risk Assessment Branch V (RA
Heal t h Effects Division (HED) (7509P)
Office of Pesticide Programs

THROUGH : Michael S. Metzger

, Chief 

# If ( J p1 

## jJ )/} / /

. Risk Assessment Branch V 

# Vvfflv1 /f · /**~** Health Effects Division (750 P)
Office of Pesticide Programs

TO : Monica Wait, Chemical Review Manager Molly Clayton, Chemical Review Manager Risk Management and Implementation Branch III (RMIB3)
Pesticide Re- E valuation Division (PRO)
Office of Pesticide Programs (7508P)

Attached is Health Effects D iv ision ' s (BED's) human health ri sk assessment s tatus update (scoping document) for the herbicides atrazine

, propazine, and simazine, as part of the registration review process.

Page 1 of29Execut i ve Summary

The HED Atrazine, Propazine, and Simazine Registration Review Team has evaluated the status
of the human health risk assessments for these triazine herbicides to determine the scope of work

necessary to support Regis t ration Review. These herbicides are being considered together in this seeping document because of their shared chloro me t abolites, hazard identification, and hazard
characterization. The most recent human-health risk assessment for atrazine was conducted in

2002 (D272009

, C. Eiden, 4 /1 6 / 2002); for propazine in 2005 (D336673, J. Morales 

### et al.,

12

/ 13/2005) ; for simazine in 2006 (D325433, D. Soderberg 

### et al., 1112/2006); and for the

triazine cumulative assessment in 2006 (D317976, C. Eiden, 3/28/2006). H E D has considered
whether updates are needed to these assessments based on current Agency science policy and

risk assessment methodologies; and after reviewing the toxicity, exposure and usage databases of

these triazine herbicides. Between 2009 and 2011, the agency held five meetings of the FIFRA
Scientific Advisory Panel (SAP) on topics related to non

- cancer and cancer effects of atra z ine

and its chloro-triazine metabolites (http://www.epa.gov / scipoly/sap / meetings / index.htm). To
support this seeping document, HED has updated the literature search for recent publications

relevant to the human health risk assessment related to experimen t al toxicology and epidemiology studies. The Agency's issue papers 1 and respective SAP reports 2 will be used to
inform updates to the hazard assessment for atrazine, propazine

, and simazine.

In accordance with the 2007 revised 40 CFR Part 158 Toxicology data requirements

, the neurotoxicity battery (acute and subchronic neurotoxicity studies) and an inhalation study are required for triazines. However, based on a weight-of-evidence (WOE) approach, considering

all the available triazine hazard and exposure information, the HED Hazard and Science Policy

Council (HASPOC) concluded that at this time no new dermal, inhalation, or neurotoxicity
studies are required for atrazine

, propazine, or simazine (K. Rury, 

### in preparation).

Residue chemistry studies submitted in response to previous data call-in requests for atrazine and

simazine are currently in review. These reviews will be completed as part of the registration
review risk assessments for the single chemicals as appropriate.

The current tolerance expressions for atrazine, propazine, and simazine should be modified in

accordance with the current policy on tolerance definitions (S. Knizner, 5 / 27 / 09). See the
Tolerance Assessment section for the recommended language.

In registration review, occupational exposure assessments will be updated to incorpora t e current occupational exposure policies

, currently registered maximum application rates, and any changes

to the toxicological endpoints. Similarly, residential exposure assessments will be updated to incorporate HED's 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment, currently registered maximum application rates, and any changes to the toxicological endpoints.

Also in registration review, updated risk estimates for exposures to residues of atrazine, propazine, and simazine and their chlorinated metabolites in drinking water will be determined

1 Issue paper citations.

2 Sap report citations.

Page 2 of29

### Page 3 of 29

for standard populations receiving their drinking water from community water systems (CWS), using the most recent results from on

- going surface and ground water monitoring data programs.

Introduction

Atrazine, propaz ine, and simazine are selective triazine herbicide s that, for the purpose of this memo, are referred to collectively as the “chlorotriazine herbicides”

. These herbicides are being considered together in this scoping document because of their shared chloro metabolites, hazard identification, and hazard characterization. They control a wide variety of broadleaf weeds and some grassy weeds.

The chlorotriazine herbicides may be grouped toget her based on a common toxicity end

- point (neuroendocrine and neuro endocrine

- related developmental and reproductive effects) and a known mechanism of toxicity for this endpoi nt. These three chemicals and their three major
chloro metabolites

, desethyl

- s

- atrazine (DEA), d esi sopropyl

- s

- atrazine (DIA), and
d iaminochlorotria zine (DACT)

, constitute the triazine common mechanism group (CMG)

. For the purpose of this memo, these six compounds are referred to collectively as the “CMG triazines”, which can caus e a disruption of the hypothalamic

- pituitary

- gonadal (HPG) ax is in the rats by alteration of levels of luteinizing hormone (LH). The grouping of the CMG triazines based on a common mechanism of action was presented to the FIFRA SAP in 2000. The SAP agreed with the Agency’s conclusion that there is sufficient evidence to sup port the proposed grouping for the neuroendocrine and neuroendocrine

- related effects (USEPA, 2000 ).

Refer to Attachment 1 for relevant nomenclature and physical properties of the chlorotriazine
herbicides

, and the chemical structures of the CMG triazine s.

Use Profile

Atrazine is registered for the control of broadleaf weeds and some grassy weeds. Atrazine is used on corn (field , pop, and sweet), sorghum, sugarcane, wheat (application to wheat stubble on fallow land following harvest), guava, macadamia nuts, hay, pasture, fallow, forestry or woodlands, conifers, woody ornamentals, Christmas trees, sod, and residential and recreational turf (parks, golf courses). Most atrazine use on lawns is in Florida and the Southeast.

Propazine is registered in the U.S. for indoor greenhouse uses and on sorghum ( predominantly
used in TX )

.

Simazine is registered for use in/on a variety of food and feed c rops in the United States

. Simazine is also used on ornamental plant s , Christmas tree farms, nursery s toc k

, building perimeters, non

- agricultural areas, shelterbelt plantings, 

### home lawns, golf courses, and turfgrass grown commercially for sod, as well as in forestry.

Atrazine is formulated for occupational use as liquid, wettable powder

, dry flowable

,
a nd granular product s

. In several formulations, atrazine is combined with other active ingredients, usually herbicides, and it is also formulated wi th fertilizer. Simazine is

### Page 4 of 29

formulated as wettable powders, emulsifiable concentrates, and flowable

concentrates. Propazine is formulated for occupational use as a liquid product.

Hazard Identification/Toxicology

For the purpose of estimating risks, the CMG triazines are assumed to be equivalent in toxicity to
atrazine

. This health

- protective assumption is based on the evaluation of endocrine

- related data
on the chloro triazine herbicide s demonstrating either equal potency or potency less than atrazin e , and minimizes the possibility of underestimating risk 3



### .

The CMG t riazines exhibit low acute toxicity via oral, dermal, and inhalation routes of exposure (Category III or IV), and are not dermal sensitizer s

.

As a result of their common mechanism of toxicity, exposure to the CMG triazine s results in reproduc tive and developmental effects that are considered relevant to humans. These effects form the basis of the regulatory endpoint selection for triazines. Th e toxic mode of action
involves centra l nervous system (CNS) toxicity ( suppression of the luteinizing hormone surge prior to ovulation resulting in prolonged estrus in adult female rats (demonstrated with atrazine and simazine) ) , and developmental delays ( delayed vaginal opening and preputial separation in developing rats (studied in atrazine but not simazine) )

. These neuroendocrine effects are considered the primary toxicological effects of regulatory concern.

In recent years, numerous governmental and academic research groups have published experimental toxicology and epidemiologic studies evaluating the toxicity profile and/or mode of action (MOA) of atrazine

. These new studies have considered a variety of adverse outcomes such as reproductive toxici ty in males and females, adverse birth outcomes, hormone disruption, neurotoxicity, immunotoxicity, respiratory health, effects on the mammary gland, and carcinogenicity. To consider the extent to which these new studies may influence the Agency’s
human h ealth risk characterization for atrazine, OPP in collaboration with the Office of R esearch and Development (ORD) has evaluated the new research on atrazine and its chloro

- s

- triazines metabolites (DEA, DIA, and DACT). Between 2009 and 2011, the agency hel d five meetings of the FIFRA Scientific Advisory Panel (SAP) on topics related to non

- cancer and cancer effects of
atrazine and its chlorinated metabolites of concern ( http://www.epa.gov/scipoly/sap/meetings/index.htm ).

The February 2010 SAP meeting (pu blic docket EPA

- HQ

- OPP

- 2009

- 0851) focused on a number of broad scientific issues related to the use of epidemiology and human incident data in risk

assessment known as the draft Framework

. The “Framework” delineated OPP’s proposed method of identifying, evaluating, and synthesizing epidemiology data within the regulatory review process, and also described issues related to the integration of both toxicology and epidemiology to inform hazard identification, characterization and exposure

- response

assessment. At this meeting, EPA also presented a case study of the preliminary evaluation and

3 USEPA (2006). Triazine Cumulative Risk Assessment . HED Human Health Risk Assessment in Support of the Reregistration Eligibility Decisions for Atrazine, Simazine and Propazine. PC Codes: 080808, 080803, 080807. DP 317976. May 28, 2006

### Page 5 of 29

synthesis of epidemiology studies concerning atrazine exposure in relation to adverse birth

outcomes

. Th e FIFRA SAPs consideration of the “Framework” as well as the case study provided useful advice to consider as OPP works to incorporate epidemiology data in risk assessment. The materials prepared and presented at this meeting h a ve informed the review of

nu merous epidemiology studies on atrazine.

The April and September 2010 SAP meeting s (public dockets EPA

- HQ

- OPP

- 2010

- 0125 and

EPA

- HQ

- OPP

- 2010

- 0481 respectively) included a review of numerous atrazine in vivo and in
vitro experimental toxicology studies as well as epidemiology evaluations concerning the non

cancer health effects of atrazine. The focus of these reviews were studies published between 2003 and January 2010; EPA had previously summarized the experimental and observational literature on this top ic in the 2002 human health risk assessment and June 2003 FIFRA SAP on
atrazine , respectively

. Based on these analyses, the agency concluded and the SAP concurred
that a ttenuation of the LH surge continues to be the most sensitive effect ( i.e., occurs at the lowest dose) identified to date in the atrazine database. Perturbations of LH signal a disruption
of the hormonal environment in the individual and serve as a sentinel effect used to establish a point of departure (PoD) for the risk assessme nt that would be health protective for the other
effects noted in the database. These other effects occur at higher doses than the LH surge attenuation and include delays in puberty onset, disrup tion of estrous cycles, and suppression of suckling

- induced prolactin release in the lactating dams, leading to prostatitis in young adult rats; they provide insight into the temporal relationship between atrazine exposure and adverse health

outcomes. Concerning the epidemiology evidence, EPA concluded and the SAP concurred that while the evidence of a possible association between atrazine exposure and non

- cancer health outcomes such as male and female reproductive health effects ( e.g. , semen quality and menstrual cycle irregularities) and adverse birth outcomes ( e .g. , preterm birth and birth malformations) could plausibly be related to the herbicide’s influence on the hypothalamic

- pituitary

- gonadal (HPG) axis observed in the toxicology data, the strength of the epidemiologic evidence was
insufficient to conclude a causal association may exist. Limitations in the epidemiology database were significant including inadequate characterization of atrazine exposure. In addition, while the observational data qualitatively support the experimental studies, the Agency will re ly upon toxicology studies to perform hazard identification and characterization as well as dose

- response assessment for non

- cancer effects in the upcoming human health risk assessment

.

At the September 2010 and July 2011 SAP meetings (public dockets EPA

- HQ

- OPP

- 2010

- 0481
and EPA

- HQ

- OPP

- 2011

- 0399 respectively) , the Agency proposed a range of exposure durations
relevant for the toxic effects of 4

- 28 days. A single value was not proposed due to uncertainties in the duration required to elicit toxic effects, p articularly in humans. The SAP commented in the December 2010 report that “the imprecision in the Agency’s proposed sampling frequency seems justified. This may be about as precise an estimate as can be obtained when starting with the experimental animal d ata and the exposure requirements for LH surge suppression...”

The CNS mechanism of toxicity also results in mammary tumors specific to female Sprague

Dawley rats exposed to chloro triazine herbicide s; however, the particular cascade of events leading to t umor formation is species, strain and sex specific

, and is not considered to be operative in humans. Consequently, atrazine has been classified as “Not Likely to be Carcinogenic to Humans”, as described in the June 2000 Scientific Advisory Panel (SAP) report. This classification also pertains to propazine and simazine. At the April 2010 SAP (public

### Page 6 of 29

docket EPA

- HQ

- OPP

- 2010

- 0125) , the Agency reviewed new experimental toxicology studies on cancer published si nce the last atrazine risk assessment in 2003. The Agency concluded, and the SAP concurred, that the new experimental toxicology studies on cancer did not alter or contradict the major key events in the neuroendocrine MOA leading to mammary gland tumors
in the rat or the conclusion that the MOA leading to mammary gland tumors in the rat is not
relevant to humans. In July 2011 (public docket EPA

- HQ

- OPP

- 2011

- 0399) , EPA presented its review of the cancer epidemiology studies for atrazine published since 2003. I n this meeting, EPA concluded the epidemiology evidence are not strong enough to warrant a change to its current cancer classification for atrazine, although SAP panel members urged the Agency to continue to follow the published cancer epidemiology lite rature with regard to ovarian, thyroid and possibly lymphohematopoietic cancers specifically. The SAP stated that although s tudies of
these anatomical cancer endpoints are inconclusive at this time, Panel members believed the data were suggestive of a pos sible association and warrant close evaluation in future assessments. During registration review, EPA will perform an up to dat e atrazine/triazine cancer epidemiology literature review in support of the human health risk assessment in consideration of the Panel’s
advice

.

Per the 2007 revised 40 CFR Part 158 Toxicology data requirements, the neurotoxicity battery (acute and subchronic neurotoxicity studies) and an immunotoxicity study are all required for the
chloro triazine herbicides

. However, HASPOC (meeting of 2/14/13) determined that acute and subchronic neurotoxicity studies are not required because th e available data for the chloro triazine
herbicides indicate that the neuro endocrine effects described above will be more sensitive than

any potential apical neurotoxicity effects seen in adult animals in the neurotoxicity studies. In an immunotoxicity study in rats with atrazine, there was no evidence of immunosuppression at the highest dose tested. Although a few recent studies in the published lite rature suggest a potential
for atrazine to affect the immune system at high doses

, the available data do not indicate
atrazine

- induced immunotoxicity is a more sensitive endpoint than the atrazine

- induced effects on neuroendocrine function, e.g., attenuati on of LH surge in female Sprague

- Dawley rats

. Thus,
based on the atrazine immunotoxicity data, studies for propazine and simazine are not necessary.

The points of departure (PoDs) and toxicity endpoints from the most recent risk assessmen t s are summarized in Attachment 3, Table 3.1. The toxicity endpoints and PoDs for risk assessment
were selected for acute and chronic dietary, and short

- and intermediate

- term dermal

, incidental oral, and inhalation scenarios. Toxicity endpoints for the ch loro triazine herbicides will be re

evalu a ted after consideration of recent studies in the published literature. With respect to the endpoint selection and relevant duration(s) of exposure, the agency plans to update the information
contained in 

### Attachment 3, Table 3.1 based on the SAP reviews from 2010 and 2011.

T here are no toxicology data gaps for the chloro triazine herbicides (Attachment 4)

.

Residue Chemistry

In response to data call

- in s for the atrazine RED (GDCI

- 080803

- 25114 and GDCI

- 080803

- 20871)

, a field accumulation in rotational crop s study was submitted (MRID 47377502 and Amended Final Report MRID 48487001). The final study report is currently in review; once complete, recommendations regarding the need for inadvertent tolerances on rotationa l crops at the desired plant

- back intervals (PBIs) will be made

.

### Page 7 of 29

In response to a data call in for the simazine RED (GDCI

- 080807

- 26426) , and as part of a
simazine new use petition (PP#2F8006), crop field trial, storage stability, field accumulation i n rotational crops, and analytical method studies have been submitted (MRID 485777

- 01 thru

- 09;
486822

- 01 thru

- 03; 488047

- 01 and 489601

- 01). These studies are currently in review. Data
Evaluation Rec or ds (DERs) with classifications will be issued upon r eview completion.

No new residue chemistry studies were required for propazine during re registration, and no
recent data have been submitted.

Dietary Exposure (food)

The 2006 triazine cumulative assessment indicate d that negligible atrazine

, propazine, and
simazine exposure s occur through foods. Thus, f ood related exposures to atrazine, propazine and
simazine were set to zero for the aggregate and cumulative triazine dietary assessment s . The rationale for this decision was based on the use p atterns for these herbicides involving pre

emergent uses as soil directed sprays and the lack of detections in the monitoring a nd crop field
trial databases. This decision will be re

- evaluat ed in registration review, taking into account the
most recent fo od monitoring and crop field trial data.

Dietary Exposure (water)

Atrazine
The occurrence of atrazine in the environment prompted the EPA ’s Office of Water (OW) to regulate atrazine under the Safe Drinking Water Act (SDWA), and in 1991 OW established a Maximum Contaminant Level (MCL) of 3 parts per billion (ppb) for atrazine. Under the SDWA, atrazine has been subject to compliance monitoring. Consequently, there are extensive water (surface and ground) monitoring data available for atrazine : more than for any other pesticide. Thus, the 2002 atrazine drinking water exposure assessment was based only on monitoring data. As c omparisons show higher total residue levels in surface water than in ground water, the 2002 dietary exposure assessments were base d on surface water monitoring data, which are protective for residues in ground water.

### Page 8 of 29

Screening

- level exposure assessments were conducted for maximum one day (acute) , 90

- day

average (intermediate

- term)

, and annual average (chronic) exposures to residues of atrazine and its chlorinated metabolites in Community Water System (CWS) data collected from 1993

- 2001, for a total of 3670 systems. For acute exposures to the relevant population subgroup, females
13

- 49 years, the maximum concentration of atrazine and its chlorinated metabolites measured in

any CWS gave risk estimates below HED’s level of concern. Based on screening criteria used

, 29 CWS (out of the pool of 3670 systems) were identified for probabilistic assessment for the
intermediate

- term exposure s cenario

. This analysis demonstrated that 90

- day average exposures
to atrazine and its chlorinated metabolites exceeded HED’s level of concern for infants in all 29 CWS. Risk estimates for these CWS ranged from 1.0

– 6.7 times the LOC. For the chronic

an alysis, e leven of these systems had annual average concentrations of atrazine and its
chlorinated metabolites that exceeded HED’s level of concern for children.

As a result of the potential risk concerns identified, further refinements in the form of ta rgeted, intensive monitoring data were requested. As part of the 2003 Interim Reregistration Eligibility Decision (IRED) for atrazine, a Memorandum of Agreement was developed for monitoring CWS in the United States. This monitoring program measures for t he presence of the CMG triazines by determining total chlorinated triazine levels. An analysis of the most recent results from this monitoring program will be included as part of the registration review risk assessments.

Simazine Monitoring data are also available for simazine. In 2006, t he monitoring data were considered adequate to evaluate water exposures in most major simazine use areas in the United States (Mid

- W est and Mid

- Atlantic S tates, and Was h ington S tate), but inadequate for California and
Florida . Thus, PRZM/EXAMS modeling results were used to assess simazine water exposures
in areas lacking sufficient monitoring data. For acute exposures to the relevant population subgroup, females 13

- 49 years, the maximum concentration of simazine and its chlorinated metabolites measured in any CWS was below HED’s level of concern , as were the peak water
concentrations from all modeling scenarios.

For intermediate

- term water exposures, consideration of both monitoring data and modeling
estimates resu lted in the identification of scenarios where HED’s level of concern was exceeded. Specifically, from the monitoring data, t wo CWS from the Midwest (Defiance City, OH and Hillsboro, IL) were identified with exce e d a nces for infants and children based on 90

- day average
simazine concentrations at these two locations

. Based on 90

- day average concentrations from
PRZM/EXAMS modeling, several simazine application scenarios exceeded HED’s level of

concern : almond uses (aerial applications only) in California, Georgia peach and nut uses (aerial and ground applications), and citrus uses in Florida ( aerial and ground applications)

. However, upon further review of the monitoring data, the Agency concluded t hat the maximum 90

- day average concentration is lower than previously calculated, and no concentrations for this CW S are of concern to the Agency.

For chronic water exposures, annual average concentrations of simazine and its two chlorinated

### Page 9 of 29

metabolites were determined from the monitoring data and modeling results. This analysis
showed n o chronic exposure risk issues from any of the CWS monitoring data.

Propazine
As n o suitable water monitoring data were available for propazine, PRZM/EXAMS water model ing results were used for the dietary exposure assessment. No risk concerns were
identified.

Cumulative Water Assessment
In the 2006 cumulative water assessment, CMG t riazine residues in drinking water sources were considered the only contributor to dietary exposure. A combination of monitoring and modeling
data was used to assess the risk from potential exposures to CMG triazine residues in water.
Based on chloro triazine herbicide usage information provided by the Biological and Eco nomic Affects Division ( BEAD ) , the following drinking water exposure scenarios were assessed since they were considered representative of high

- end exposures to the CMG triazines: 1) Mid

- W est using monitoring data, 2) California using modeling data, and 3) Florida using modeling data.

Data from a pool of 118 CWS using surface water monitored from 2002

- 2004 for the CMG triazines were used for the cumulative drinking water assessment in the Mid

- W est. The 118 CWS were ranked from high to low for peak conce ntrations (from 90

- day rolling average exposures) of total CMG triazines. The 15 highest CWS were further analyzed using probabilistic model ing , which showed no risk levels exceeded EPA’s level of concern for the
four most vulnerable and sensitive populat ion subgroup s identified : infants < 1 year old,
children 1

- 2 years old, females 13

- 49 years old, and males 20

- 49 years old.

Risk estimates for the California and Florida scenarios were ba sed on PRZM/EXAMS modeling data, modified by a cumulative adjustmen t factor (CAF) to account for portions of the simulated
watershed that are not treated with atrazine and/or simazine. M odeled 90

- day average exposures

were utilized to determine risk estimates for the same four population subgroups discussed
above. No ri sk concern for any population subgroup was found

.

For the Florida and California drinking water exposure scenarios, PRZM/ EXAMS modeling
estimates were used in previous assessments. As part of registration review, the Agency will determine if any updates to the water modeling estimates are appropriate , or if there are sufficient monitoring data available for these states.

Residential Exposure

Registered residential uses for atrazine and simazine (no residential use for propaz ine) include application to residential turfgrass, ornamentals, and recreational turf areas. The duration of exposure is expected to be short

- term (1

- 30 days) only; intermediate

- and long

- term exposures are not anticipated. The level of concern (LOC) for risk estimates is a margin of exposure (MOE) of less than 100 for short

- term dermal, inhalation and oral exposure. Existing residential handler and post

- application exposure and risk assessments do not show risk estimates of

concern.

### Page 10 of 29

Turf Transferable Residue (TTR): There are several TTR studies available for atrazine and
simazine that will be used to assess residential post

- application scenarios.

There is sufficient information available to assess residential exposure. Previous re sidential exposure assessments for atrazine and simazine did not identify any scenarios that exceeded HED’s level of concern. However, as new residential SOPs containing additional turf scenarios have recently been finalized, the residential exposure asse ssments for atrazine and simazine will be updated in the registration review risk assessments. Any changes to toxicity endpoints and/or safety factors will also be included in these updates.

Aggregate Risk Assessment

A ggregate risk assessment s evaluate the combined risk from dietary exposure (food and water) and any non

- occupational (residential) uses. Separate assessments may be conducted to include relevant exposure durations: acute, chronic, short

- , intermediate

- , and long

- term. Separate

a ggregate risk assessments have been conducted for atrazine, simazine, propazine

, and the
CMG triazines.

For atrazine and simazine

, acute aggregate risk estimates were the same as those for the acute drinking water assessment. E xposures from residential turf use s were aggregated with dietary exposures for a short

- term aggregate risk assessment

. No intermediate

- term nor long

- term exposures to atrazine or simazine are ex pected for residential uses. Thus, a quantitative
intermediate

- term assessment is not required, and chronic aggregate risk estimates were the same as those for the chronic drinking water assessment s

.

Since t here are no registered residential uses of propazine, its aggregate assessment consists of the dietary exposure (water only) assessment

.

During registration review, updated aggregate assessments may be conducted to include any updates to toxicological endpoints, dietary exposure estimates, and changes to residential SOPs.

Occupational Exposure

The chlorotriazine herbicides 

### are registered for uses on agricultural crops and non

- crop areas. The durations of exposure are expected to be short

- term (1

- 30 days) and intermediate

- term (1

- 6 months); long

- term exposures are not anticipated. The Agency’s LOC for short

- and
intermediat e

- term dermal and inhalation risk estimates is 100; i.e., MOEs below 100 are of concern to the Agency. Occupational handler and post

- application exposure and risk

assessments were conducted on the registered occupational (agricultural and non

- crop) uses, resulting in risk estimates that are not of concern for the majority of scenarios. For those

s cenarios w ith risk estimates below 100 that exceeded HED’s level of concern, risk mitigation steps were taken (i.e., reduction in application rate). As a result of risk mitigation

, new supplemental labels were created for some atrazine and simazine products.

The current HED policy incorporates new scenarios that were not previously assessed (e.g. handheld equipment for turf and ornamentals) ; all relevant occup ational exposure scenarios will

### Page 11 of 29

be considered when the registration review risk assessments are prepared

.

Dislodgeable Foliar Residue (DFR): There are several DFR stud ies available for the
chloro triazine herbicides; these will be considered in assessing postapplication risk for re

- entry scenarios.

There is sufficient information available to assess occup ational handler and post

- application exposures. In registration review, a n up

- to

- date quantitative occupational risk assessment may be required to account for c urrent registered application rates, unit exposures, transfer coefficients (TCs), and toxicity endpoints and safety factors.

Endocrine Disruptor Screening Program

As required by the Federal Insecticide, Fungicide, and Rodenticide Act (FIF RA) and the Federal Food, Drug, and Cosmetic Act (FFDCA), EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of ca rcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in
diffe rent taxonomic groups. As part of its most recent registration decision , EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408 (p), atrazine, simazine and propazine are subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) ma y have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required
determi nations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to h ave the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adve rse endocrine

- related effects caused by the substance, and
establish a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2 010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Atrazine and
simazine are among the group of 58 pesticide active ingredients on the initial list to be s creened
under the EDSP

. Once all required Tier 1 as say s have been received and reviewed, the endpoints

### Page 12 of 29

and safety factors used for risk assessment purposes will be examined and a new risk assessment performed if necessary. P ropazine was not included in t he initial list. Accordingly, as part of registration review, EPA will issue future EDSP orders/data call

- ins, requiring the submission of EDSP screening assays for propazine . For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

Public Health and Pesticide Epidemiology Data

The April and September 2010 SAP meetings (public dockets EPA

- HQ

- OPP

- 2010

- 0125 and

EPA

- HQ

- OPP

- 2010

- 0481 respectively) included a review of epidemiology evaluations concerning the non

- cancer health effects of atrazine. EPA concluded

, and the SAP concurred

, that while the evidence of a possible association between atrazine exposure and non

- cancer health outcomes such as male and female reproductive health effects ( e.g. , semen quality and menstrual cycle irregularities) and adverse birth outcomes ( e.g. , prete rm birth and birth malformations) could plausibly be related to the herbicide’s influence on the hypothalamic

pituitary

- gonadal (HPG) axis observed in the toxicology data, the strength of the epidemiologic
evidence was insufficient to conclude a causal ass ociation may exist. Significant limitations in the epidemiology database were noted, including inadequate characterization of atrazine

exposure.

In the July 2011 SAP meeting (public docket EPA

- HQ

- OPP

- 2011

- 0399) , EPA concluded the epidemiology evidence ar e not strong enough to warrant a change to its current cancer classification for atrazine, although SAP panel members urged the Agency to continue to follow the published cancer epidemiology literature with regard to ovarian, thyroid and possibly lymphohem atopoietic cancers. The SAP stated that although studies of these anatomical cancer endpoints are inconclusive at this time, the data were suggestive of a possible association and
warrant close evaluation in future assessments. EPA will perform up to dat e atrazine/triazine cancer epidemiology literature review s in support of the human

- health risk assessment in
consideration of the Panel’s advice.

Based on the low frequency and severity of incident cases reported for atrazine, propazine and
simazine to b oth the OPP Incident Data System ( IDS ) and the National Institute for Occupational Safety and Health Sentinel Event Notification System for Occupational Risk

– Pesticides ( NIOSH SENSOR

- Pesticides ) , there does not appear to be a concern at this time that wo uld warrant further investigation (D407491, S. Recore, 1/22/13)

. T he A gency will continue to monitor the incident information and if a concern is triggered, additional analysis will be also be
included at that time.

Tolerance Assessment and International Harmonization

A summary of US tolerances for residues of atrazine, propazine, and simazine may be found in
Attachment 2

. N o Codex M aximum R esidue L imits (MRLs) have been established for atrazine, propazine, or simazine in/on any commodity

. Mexico generally adopts US tolerances and/or Codex MRLs for export purposes. Canada has established MRLs for atrazine that are harmonized with US tolerances except for meat, milk, poultry and egg (MMPE) commodities.

### Page 13 of 29

For MMPE commodities , either the US tolerance is less than the Canadian MRL, or no US
tolerance has been established.

Tolerances are established under 40 CFR §180.220 for the combined residues of atrazine and
its three chlorinated metabolite s in/on a variety of crops and livestock commodities. HED recommends that the residue definition for the tolerance expression for atrazine be modified i n accordance with current policy on tolerance definitions (S. Knizner, 5/27/09), to read:

“ Tolerances are established for residues of the herbicide atrazine

, including its metabolites and degradate s , in or on the commodities in the table below. Compliance
with the tolerance levels specified below is to be determined by measuring only the sum of atrazine

, 6

- chloro

- N

- ethyl

- N′

- (1

- methylethyl)

- 1,3,5

- triazine

- 2,4

- dia mine

, its desethyl
metabolite 2

- amino

- 4

- chloro

- 6

- isopropylamino

- s

- triazine (G

- 30033) ( DEA)

, its desisopropyl metabolite 2

- amino

- 4

- chloro

- 6

- ethylamino

- s

- triazine (G

- 28279 ) (DIA )

, and
its diamino metabolite 2,4

- diamino

- 6

- chloro

- s

- triazine (G

- 28273) (DACT)

, c alculated as the stoichiometric equivalent of atrazine , in or on the commodity.”

Tolerances are established under 40 CFR §180.243 for residues of propazine in/on sorghum
commodities. HED recommends that the residue definition for the tolerance expression for propazine be modified i n accordance with current policy on tolerance definitions , to read:

“ Tolerances are established for residues of the herbicide propazine

, including its
metab olites and degradate s , in or on the commodities in the table below. Compliance
with the tolerance levels specified below is to be determined by measuring only the sum of prop a zin e, 6

- chloro

- N

, N ’

- bis(1

- methylethyl)

- 1,3,5

- triazine

- 2,4

- diamine , its desisoprop yl metabolite 2

- amino

- 4

- chloro

- 6

- isopropylamino

- s

- triazine (G

- 30033) (DEA), and its diamino metabolite 2,4

- diamino

- 6

- chloro

- s

- triazine (G

- 28273) (DACT)

, calculated as the stoichiometric equivalent of propazine, in or on the commodity.”

Tolerances are esta blished under 40 CFR §180.213 for the combined residues of simazine and
its two chlorinated metabolites in/on a variety of crops and livestock commodities. HED recommends that the residue definition for the tolerance expression for simazine be modified i n accordance with current policy on tolerance definitions , to read:

“ Tolerances are established for residues of the herbicide simazin e, including its metabolites and degradate s , in or on the commodities in the table below. Compliance
with the tolerance levels specified below is to be determined by measuring only the sum of sim azine

, 6

- chloro

- N,N’

- diethyl

- 1,3,5

- triazine

- 2,4

- diamine , its des ethyl metabolite 2

- amino

- 4

- chloro

- 6

- ethylamino

- s

- triazine (G

- 28279) (DIA) , and its diamino metabolite 2,4

- diamino

- 6

- c hloro

- s

- triazine (G

- 28273) (DACT)

, calculated as the stoichiometric equivalent of simazine, in or on the commodity.

Environmental Justice

### Page 14 of 29

Potential areas of environmental justice concerns, to the extent possible, were considered in this
human health ris k assessment, in accordance with US Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," http://www.eh.doe.gov/oe pa/guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pestic ide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under t he Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and reg ion of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of p esticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas
post

- application are evaluated. Further considerations are currently in development as OPP has
committed resources and e xpertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups

.

Cumulative

For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity

, and how 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/.

In assessing cumulative risks, EPA evaluates the potential fo r people to be exposed to more than one pesticide at a time from a group with an identified common mechanism of toxicity. These
cumulative assessments consider exposures from all relevant pathways and routes of exposure to
all chemicals in a common mechan ism group

. The Agency incorporates regional exposures from residential and drinking water sources since this is the most appropriate way to account for the considerable variation in potential exposures across the country. EPA's cumulative assessments,
th erefore, est imate actual exposures and potential risks resulting from current uses of these pesticides in different parts of the country.

EPA followed a cumulative risk approach based on a common mechanism of toxicity for the
CMG triazines. In the most r ecent cumulative risk assessment, issued on June 21, 2006, the

agenc y evaluated water

- only for the M idwest, California and Florida using a 90

- day rolling average approach based on attenuation of LH from an atrazine study as the toxicity endpoint

, and
also evaluated multi

- pathway exposure from water and residential turf exposure in Florida using
a 28

- day rolling average

, and a 28

- day pubertal atrazine study in rats. Thus, risk estimates from residential turf and drinking water exposures to atrazine and sima zine were summed for Florida

### Page 15 of 29

only.

Results of probabilistic modeling demonstrated that cumulative risks were below HED’s level of concern for the most vulnerable and sensitive population subgroups at the 99.9 th 

### percentile of

exposure. The majority of t he cumulative exposure was from residential dermal exposure. Additional information and supporting documentation for the 2006 triazine cumulative assessment can be found in the public docket EPA

- HQ

- OPP

- 2005

- 0481.

The 2006 cumulative risk assessment for the CMG triazines demonstrated no risk levels exceeding HED’s level of concern. EPA anticipates updating the cumulative risk assessment during registration review to take into consideration recent monitoring and exposure da ta and any changes to toxicity endpoints and models or assessment methodologies.

-

Human Studies

Past chlorotriazine herbicide risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as the Pesticide Handlers Exposure Database (PHED) and the Agricultura l Reentry Task Force (ARTF) Database. EPA has reviewed all the studies supporting these multi

- pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or signif icantly deficient relative to the ethical standards prevailing at the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulat ory barrier to continued reliance on these studies.

Data Requirements

As shown in Reference s below, the most recent human health risk assessments for atrazine, propazine, and simazine were conduct ed between 2002 and 2007

. Provided the submitted
residue chemistry data are found to be acceptable, t here are no outstanding data gaps associated with the toxicology , exposure and residue chemistry requirements.

References

Memoranda Relevant to Registration Review of Triazines
Author Barcode

(DP#) Date Title

Risk Assessments
C. Eiden D272009 4/16/2002 Atrazine. HED’s Revised Human Health Risk Assessment for the Reregistration Eligibility Decision (RED).

C. Eiden D317976 3 /28 /2006 Cumulative Risk from Triazine Pesticides

J. Morales et
al. D323271 12/13/2005 Propazine. Revised HED Risk Assessment for the Tolerance Reassessment Eligibility Decision Document (TRED) Which Includes a New Use on Grain Sorghum.

### Page 16 of 29

Memoranda Relevant to Registration Review of Triazines
Author Barcode

(DP#) Date Title

D. Soderberg
et al. D325433 1/12/ 2006 Simazine. Revised HED Chapter of the Reregistration Eligibility decision Document (RED); Revised for Public Comments and to
Correct SWLOC Values. Incident Reports

S. Recore & E.

Evans D407491 1/22/2013 Atrazine, Propazine, and Simazine: Review of Human Incidents

Residue Chemistry
C. Eiden & D. Soderberg D272006 4/16/2002 Atrazine. HED Product and Residue Chemistry Chapters.

J. Morales D 308537 8/31/2005 Propazine. Residue Chemistry Summary for the Tolerance Reassessment Eligibility Decision Document (TRED) and a Proposal To Reinstate Food/Feed Use on Grain Sorghum

. D. Soderberg D326105 2/1/2006 SIMAZINE: Residue Chemistry Chapter for the RED, Revised to repair some inconsistencies in Table 11 compared to the rest of the text in the Chapter

. Occupational Residential Exposure Gary Bangs D282457 4/25/2002 ATRAZINE: Revised Occupational and Residential Exposure Assessment and Recommendations for the Reregistration Eligibility Decision Document

Steven Weiss D316475 05/31/2005 SIMAZINE: Occupational and Residential Exposure
Assessment and Recommendations for the Reregistration Eligibility Decision Document

Steven Weiss D308535 08/31/2005 PROPAZINE: Occupational and Residential Exposure Assessments for the Proposed Sorghum Use and the Existing Greenhouse Uses Updated with New Toxicity Endpoints



### Attachments 1. Chemical Identity Tables 2. Tolerance Summary Table s 3 . Endpoint Selection Table
4

. Toxicology Data Requirements

### Page 17 of 29 At tachment 1

Chemical Identity Table s

TABLE 1 .1. Atrazine Nomenclature. Compound

Common name Atrazine Company experimental name G

- 30027

IUPAC name 6

- Chloro

- N

- ethyl

- N

- isopropyl

- [1,3,5]triazine

- 2,4

- diamine

CAS name 6

- chloro

- N

- ethyl

- N′

- (1

- methylethyl)

- 1,3,5

- triazine

- 2,4

- diamine CAS registry number 1912

- 24

- 9

End

- use product (EP) AAtrex® 4L

TABLE 1 .2 Physicochemical Properties of Atrazine.

Parameter Value References Melting point/range 176.0o C MRID 00142160, 00164822, 43337901, 230302, Ciba Analytical Test #AG

- 87, Syngenta Study #1744

- 02 pH 7.0 at 25o C Relative Density (20oC) 0.37 g/cm 3

Water solubility (20oC) 0.033 g/L Solvent solubility (g/100 mL at 20oC) Solvent grams/100 mL solvent
Acetone 3.2
Octanol 0.92
Ethanol 1.11
Toluene 0.42
Hexane 0.01 Vapor pressure 2.89 x 10 - 7 mm Hg Dissociation constant, pK

a PKa = 1.60 @ 20o C Octanol/water partition coefficient, Log(K OW ) 481 (log P

ow = 2.68) at 25o C

Table 1.3 Propazine Nomenclature.

Compound

Common name Propazine
Company experimental name Not available

IUPAC name 6

- chloro

- N 2

, N 4

- di

- isopropyl

- 1,3,5

- triazine

- 2,4

- diamine

CAS name 6

- chloro

- N

, N ’

- bis(1

- methylethyl)

- 1,3,5

- triazine

- 2,4

- diamine

CAS # 139

- 40

- 2

### Page 18 of 29

TABLE 1.4 Physicochemical Properties of Propazine.

Parameter Value Reference 1

Melting point 217.7 C RD D219079, 9/26/95, S.
Malak pH 5.66

Density 0.46 g/mL
Water solubility 3.8 ppm at 25 C

Solvent solubility (at 25°C) 14,252 ppm in acetone 4,696 ppm in 1

- octanol Vapor pressure 2.9 x 10
- 8 mm Hg at 20 C

2.98 x 10
- 5 Torr at 45 C Product Chemistry Chapter
of the Propazine Reregistration Standard,
5/19/87

RD D219079, 9/26/95, S.
Malak Dissociation constant (pK

a ) Not applicable; practically insoluble in water RD D219079, 9/26/95, S.
Malak Octanol/water partition coefficient Log(K OW ) P = 1234.7 Log P = 3.08

TABLE 1 .5 Simazine Nomenclature.

Chemical Structure

Empirical Formula C 7 N 5 H 12 Cl

Common name Simazine

Company experimental name G27692

IUPAC name 6

- chloro

- N 2 ,N 4

- diethyl

- 1,3,5

- triazine

- 2,4

- diamine

Other Systematic 2

- chloro

- 4,6

- bis(ethylamino)

- s

- triazine

CAS name 6

- chloro

- N,N’

- diethyl

- 1,3,5

- t riazine

- 2,4

- diamine

CAS Registry Number 122

- 34

- 9

End

- use product/EP Amizine, Gesapun, Primatol S, Princep,

Chemical Class triazine herbicide

TABLE 1 .6 Physicochemical Properties of Simazine.

Parameter Value Reference

### Page 19 of 29

TABLE 1 .6 Physicochemical Properties of Simazine.

Parameter Value Reference

Molecular Weight 201.7

Melting point/range 225

- 227 C Simazine Registration Standard 1989

pH 6

- 7 Simazine Registration Standard 1989

Density (specific gravity) 1.21 at 20 C Simazine Registration Standard 1989

Water solubility (20 C) 5 ug/g Simazine Registration Standard 1989

Solvent solubility (temperature not specified) 400 ppm in methanol at 20 C 3 ppm in n

- pentane at 25 C 300 ppm in diethyl ether at 25 C 900 ppm in chloroform at 20 C 100 mg/20 mL in tetrahydrofuran Simazine Registration Standard 1989

Table 1.7 . Structures of Chlorotriazine Metabolites
Metabolite Structure

G30033 Desethyl Atrazine (DEA)

G28279 Desisopropyl Atrazine (DIA)

GG28273
Diamino chlorotriazine (DACT)

### Page 20 of 29 Attachment 2
Tolerance/MRL Table



### Atrazine (PC Code 080803 )

Table2.1 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 Codex

40 CFR § 180.220

(a) General : combined residues of the herbicide atrazine (2

- chloro

- 4

- ethylamino

- 6

- isopropylamino

- s

triazine) and its chlorinated
metabolites 2

- amino

- 4

- chloro

- 6

- isopropylamino

- s

- triazine, 2

- amino

4

- chloro

- 6

- ethylamino

- s

- triazine, and 2,4

- diamino

- 6

- chloro

- s

- triazine 6

- chloro

- N

- ethyl

- N'

- (1

- methylethyl)

- 1,3,5

- triazine

- 2,4

- diamine, including the metabolites 1,3,5

- triazine

- 2,4

- diamine, 6

- chloro

- ; 1,3,5

- triazine

- 2,4

- diamine, 6

- chloro

- N

- ethyl

- and 1,3,5

- triazine

- 2,4

- diamine, 6

- chloro

- N

- (1

- methylethyl)

- None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 Codex
Cattle, fat 0.02 0.04 Cattle, meat 0.02 0.04

Cattle, meat byproducts 0.02 0.04 Corn, field, forage 1.5 Corn, field, grain 0.20 0.2 Corn, field, stover 0.5 Corn, pop, forage 1.5 Corn, pop, grain 0.20 0.2 Corn, pop, stover 0.5 Corn, sweet, forage 15 Corn, sweet, kernel plus cob
with husks removed 0.20 0.2

Corn, sweet, stover 2.0 Goat, fat 0.02 0.04 Goat, meat 0.02 0.04 Goat, meat byproducts 0.02 0.04 Grass, forage 4.0 Grass, hay 4.0

Guava 0.05 Horse, fat 0.02 0.04 Horse, meat 0.02 0.04 Horse, meat byproducts 0.02 0.04

Milk 0.02 0.04 Nut, macadamia 0.20 Sheep, fat 0.02 0.04 Sheep, meat 0.02 0.04 Sheep, meat byproducts 0.02 0.04 Sorghum, forage, forage 0.25 Sorghum, grain, forage 0.25 Sorghum, grain, grain 0.20

### Page 21 of 29

Table2.1 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 Codex Sorghum, grain, stover 0.50 Sugarcane, cane 0.20 Wheat, forage 1.5 Wheat, grain 0.10 Wheat, hay 5.0 Wheat, straw 0.50 MRLs With No US Equivalent Eggs 0.04 Fat of Hogs 0.04 Meat of hogs 0.04

Me at byproducts of hogs 0.04

F at of p oultry 0.04 Meat of poultry 0.04

Me at byproducts of poultry 0.04

Completed: M. Negussie; 10/30/2012

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes. (d) Indirect or inadvertent residues. Tolerances are established for indirect or inadvertent residues of atrazine, 2

- chloro

- 4

- ethylamino

- 6

- isopropylamino

- s

- triazine, in or on the following raw agricultural commodity when present therein as a result of application of atrazine to the growing crops in paragraph (a) of this section:

Commodity Parts p er million

Vegetable, leafy, except brassica, group 4 0.25

### Page 22 of 29



### Propa zine (PC Code 08080 8 )

Table 2.3 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 Codex

40 CFR § 180. 243

(a) General : the sum of propazine,
2

- chloro

- 4,6

- bis(isopropylamino)

- s

- triazine, and its two chlorinated degradates, 2

- amino

- 4

- chloro

- 6

- isopropylamino

- s

- triazine and 2,4

- diamino

- 6

- chloro

- s

- triazine,
calculated as the stoichiometric equivalent of propazine None None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 Codex Sorghum, grain, forage 0.25 Sorghum, grain, grain 0.25
Sorghum, grain, stover 0.25
Completed: M. Negussie; 10/30/2012

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

### Page 23 of 29



### Sima zine (PC Code 08080 7 )

Table2.2 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 Codex

4 0 CFR § 180.2 13

(a) General : combined residues of the herbicide simazine (2

- chloro

4,6

- bis(ethylamino)

- s

- triazine) and its two chlorinated degradates (2

- amino

- 4

- chloro

- 6

- ethylamino

- s

triazine and 2,4

- diamino

- 6

- chloro

- s

triazine) None None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 Codex 2

Almond 0.25 Almond, hulls 0.25 Apple 0.20

Avocado 0.20 Blackberry 0.20 Blueberry 0.20 Cattle, meat 0.03 Cattle, meat byproducts 0.03 Cherry 0.25 Corn, field, forage 0.20 Corn, field, grain 0.20 Corn, field, stover 0.25 Corn, pop, grain 0.20 Corn, pop, stover 0.25 Corn, sweet, forage 0.20 Corn, sweet, kernel plus cob
with husks removed 0.25

Corn, sweet, stover 0.25 Cranberry 0.25

Currant 0.25 Egg 0.03 Goat, meat 0.03 Goat, meat byproducts 0.03 Grape 0.20 Grapefruit 0.25

Hazelnut 0.20 Horse, meat 0.03 Horse, meat byproducts 0.03

Lemon 0.25 Loganberry 0.20

Milk 0.03 Nut, macadamia 0.25

Olive 0.20 Orange 0.25

Peach 0.20

Pear 0.25

Pecan 0.20

### Page 24 of 29

Table2.2 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 Codex

Plum 0.20 Raspberry 0.20 Sheep, meat 0.03 Sheep, meat byproducts 0.03 Strawberry 0.25

Walnut 0.2

Completed: M. Negussie; 10/30/2012

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

### Page 25 of 29 Attachment 3

Summary of Endpoints, Points of Departure , and Toxicology Data Requirements for
Atrazine
, Propazine , and Simazine.

Table 3 .1 Summary of Toxicological Doses and Endpoints for Atrazine, Propazine, and Simazine Used in the Most Recent
Human

- Health Risk Assessments.

Exposure Scenario Dose used in Risk Assessment, UF FQPA SF and Level of Concern for

Risk Assessment Study and Toxicological Effects

Atrazine Acute Dietary (females 13

- 49) Developmental
NOAEL = 1 0 mg/kg/day
UF = 100
Acute RfD = 0.1 mg/kg/day 1X for hazard

- based

concerns. 3X for exposure

- based concerns if atrazine monitoring data used; 1X otherwise.

aPAD = aRfD/FQPA SF
aPAD = 0. 1 mg/kg/day (modeling)
aPAD = 0.033 mg/kg/day (monitoring) Developmental toxicity study in rat & rabbit (weight of evidence from four studies) w/
atrazine.

Delayed ossification of certain cranial bones in fetuses (LOAEL = 70 mg/kg/day). Decreased body weight gain in adult (LOAEL = 70 mg/kg/day).

Propazine Acute Dietary (females 13

- 49) Developmental
NOAEL = 10 mg/kg/day
UF = 100
Acute RfD = 0.1 mg/kg/day 1X for h azard

- based

concerns. 3X for exposure

- based concerns if propazine monitoring data used; 1X otherwise.

aPAD = aRfD/FQPA SF
aPAD = 0. 1 mg/kg/day (modeling)
aPAD = 0.033 mg/kg/day (monitoring) Development study in rats w/ propazine

LOAEL = 100 mg/kg/day
based on decreased ossification

Simazine Acute Dietary (females 13

- 49) Developmental
NOAEL = 30 mg/kg/day
UF = 100
Acute RfD = 0.3 mg/kg/day 1X for hazard

- based

concerns. 3X for exposure

- based concerns if simazine monitoring data used; 1X otherwise.

aPAD = aRfD/FQPA SF
aPAD = 0.3 mg/kg/day (modeling)
aPAD = 0.1 mg/kg/day (monitoring) Development study in rats w/ simazine

LOAEL = 300 mg/kg/day b ased on increased incidence of unossified teeth, head, centra vertebrae, sternabrae, and also on rudimentary ribs

Acute Dietary (general population) No toxic effect attributable to a single dose was identified for the general population

Chronic Dietary (all populations) NOAEL = 1.8 mg/kg/day
UF = 100
Chronic RfD = 0.018 mg/kg/day 10Xfor residual hazard

- based and

e xposure

- based uncertainties cPAD = cRfD/FQPA SF cPAD = 0.0018 mg/kg/day 6

- month LH surge study in rat w/
Atrazine LOAEL = 3.65 mg/kg/day based on estrous cycle alterations and LH surge suppression

Incidental Oral Short

- Term NOAEL = 6.25 mg/kg/day
UF = 100 3X for residual h azard

- based concerns

LOC is an MOE of 300 for Residential Exposure 2 8

- day Pubertal study in rats w/ Atrazine LOAEL = 12.5 mg/kg/day based on delayed preputial separation

Incidental Oral Intermediate

Term NOAEL = 1.8 mg/kg/day
UF = 100 3X for residual h azard

- based concerns

LOC is an MOE of 300 for Residential Exposure 6

- month LH surge study in rat w/
Atrazine LOAEL = 3.65 mg/kg/day based on estrous cycle alterations and LH surge suppression

Dermal short

- term NOAEL = 6.25 mg/kg/day

UF = 100 3X for residual h azard

- based concerns

LOC is an MOE of 300 for Residential Exposure
LOC is an MOE of 100 for Occupational Exposure 28

- day Pubertal study in rats w/ Atrazine

LOAEL = 12.5 mg/kg/day based on delayed preputial separation

Dermal intermediate and long

term NOAEL = 1.8 mg/kg/day 3X for residual h azard

- based concerns

LOC is an MOE of 300 for Residential 6

- month LH surge study in rat w/
Atrazine

### Page 26 of 29

Table 3 .1 Summary of Toxicological Doses and Endpoints for Atrazine, Propazine, and Simazine Used in the Most Recent
Human

- Health Risk Assessments.

Exposure Scenario Dose used in Risk Assessment, UF FQPA SF and Level of Concern for

Risk Assessment Study and Toxicological Effects

UF = 100 Exposure

LOC is an MOE of 100 for Occupational Exposure LOAEL = 3.65 mg/kg/day based on estrous cycle alterations and LH surge suppression

Inhalation short

- term NOAEL = 6.25 mg/kg/day
UF = 100 3X for residual h azard

- based concerns

LOC is an MOE of 300 for Residential Exposure
LOC is an MOE of 100 for Occupational Exposure 28

- day Pubertal study in rats w/ Atrazine LOAEL = 12.5 mg/kg/day based on delayed preputial separation

Inhalation intermediate and long

- term NOAEL = 1.8 mg/kg/day

UF = 100 3X for residual h azard

- based concerns

LOC is an MOE of 300 for Residential Exposure
LOC is an MOE of 100 for Occupational Exposure) 6

- month LH surge study in rat w/
Atrazine

LOAEL = 3. 65 mg/kg/day based on estrous cycle alterations and LH surge suppression

Dermal absorption = 6% (based on human data for atrazine)

Cancer (oral, dermal, inhalation) Classification: Atrazine, propazine, and simazine are classified as “not likely to be carcinogenic to
humans.”

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

### Page 27 of 29 Attachment 4

Toxicology Data Requirements

The requirements (40 CFR 180.220 ) for food uses of atra zine are in Table 4.1 . Use of the new guideline numbers does not imply that the new guideline protocols were used.

Table 4.1 Summary of Toxicological Data Requirements for Atr azine

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity
870.1200 Acute Dermal Toxicity 870.1300 Acute Inhalation Toxicity 870.2400 Primary Eye Irritation 870.2500 Primary Dermal Irritation
870.2600 Dermal Sensitization yes

yes

yes

yes

yes
yes yes

yes

yes

yes

yes
yes

870.3100 Oral Subchronic (rodent)
870.3150 Oral Subchronic (nonrodent)
870.3200 21

- Day Dermal
870.3250 90

- Day Dermal
870.3465 90

- Day Inhalation* yes
yes
yes
yes
yes yes

yes waived
waived

waived

870.3700a Developmental Toxicity (rodent) 870.3700b Developmental Toxicity (nonrodent) 870.3800 Reproduction yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent) 870.4100b Chronic Toxicity (nonrodent) 870.4200a Oncogenicity (rat) 870.4200b Oncogenicity (mouse) 870.4300 Chronic/Oncogenicity yes

yes

yes

yes
yes yes

yes
yes
yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial 870.5300 Mutagenicity

— Gene Mutation

- mammalian 870.5385 Mutagenicity

— Mammalian Bone Marrow
Chromosome Aberration Aberrations
870.5550 Mutagenicity

— Unscheduled DNA Synthesis yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.6200a Acute Neurotoxicity Screening Battery (rat)
870.6200b 90

- Day Neurotoxicity Screening Battery (rat) 870.6300 Developmental Neurotoxicity yes

yes

yes waived

waived

yes

870.7485 General Metabolism
870.7600 Dermal Penetration
870.7800 Immunotoxicity yes

CR

yes yes

yes

yes

### Page 28 of 29

The requirements (40 CFR 180.243) for food uses of propazine are in Table 4.2. Use of the new guideline numbers does not imply that the new guideline protocols were used.

Table 4.2 Summary of Toxicological Data Requirements for Propazine

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity 870.1200 Acute Dermal Toxicity 870.1300 Acute Inhalation Toxicity 870.2400 Primary Eye Irritation 870.2500 Primary Dermal Irritation
870.2600 Dermal Sensitization yes

yes

yes

yes

yes
yes yes

yes

yes

yes

yes
yes

870.3100 Oral Subchronic (rodent) 870.3150 Oral Subchronic (nonrodent)
870.3200 21

- Day Dermal
870.3250 90

- Day Dermal
870.3465 90

- Day Inhalation* yes
yes
yes
yes
yes yes

yes waived
waived

waived

870.3700a Developmental Toxicity (rodent) 870.3700b Developmental Toxicity (nonrodent) 870.3800 Reproduction yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent) 870.4100b Chronic Toxicity (nonrodent) 870.4200a Oncogenicity (rat) 870.4200b Oncogenicity (mouse)
870.4300 Chronic/Oncogenicity yes

yes

yes

yes
yes yes

yes
yes
yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial 870.5300 Mutagenicity

— Gene Mutation

- mammalian 870.5385 Mutagenicity

— Mammalian Bone Marrow
Chromosome Aberration Aberrations 870.5550 Mutagenicity

— Unscheduled DNA Synthesis yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.6200a Acute Neurotoxicity Screening Battery (rat)
870.6200b 90

- Day Neurotoxicity Screening Battery (rat) 870.6300 Developmental Neurotoxicity yes

yes

yes waived

waived

yes

870.7485 General Metabolism
870.7600 Dermal Penetration
870.7800 Immunotoxicity yes

CR

yes yes

yes

yes

### Page 29 of 29

The requirements (40 CFR 180.213) for food uses of simazine are in Table 4.3. Use of the new guideline numbers does not imply that the new guideline protocols were used.

Table 4.3 Summary of Toxicological Data Requirements for Simazine

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity 870.1200 Acute Dermal Toxicity 870.1300 Acute Inhalation Toxicity 870.2400 Primary Eye Irritation 870.2500 Primary Dermal Irritation
870.2600 Dermal Sensitization yes

yes

yes

yes

yes
yes yes

yes

yes

yes

yes
yes

870.3100 Oral Subchronic (rodent) 870.3150 Oral Subchronic (nonrodent)
870.3200 21

- Day Dermal
870.3250 90

- Day Dermal
870.3465 90

- Day Inhalation* yes
yes
yes
yes
yes yes

yes waived
waived

waived

870.3700a Developmental Toxicity (rodent) 870.3700b Developmental Toxicity (nonrodent) 870.3800 Reproduction yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent) 870.4100b Chronic Toxicity (nonrodent) 870.4200a Oncogenicity (rat) 870.4200b Oncogenicity (mouse) 870.4300 Chronic/Oncogenicity yes

yes

yes

yes
yes yes

yes
yes
yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial 870.5300 Mutagenicity

— Gene Mutation

- mammalian 870.5385 Mutagenicity

— Mammalian Bone Marrow
Chromosome Aberration Aberrations 870.5550 Mutagenicity

— Unscheduled DNA Synthesis yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.6200a Acute Neurotoxicity Screening Battery (rat)
870.6200b 90

- Day Neurotoxicity Screening Battery (rat) 870.6300 Developmental Neurotoxicity yes

yes

yes waived

waived

yes

870.7485 General Metabolism
870.7600 Dermal Penetration
870.7800 Immunotoxicity yes

CR

yes yes

yes

yes