UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460



# -

OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

Da te: September 25, 2014

Sub j ect:Paraquat Dichloride. HED Human Hea l th Risk Assessment for the Expansion of Representative Commodity Use on Po tato to Tuberous and Corm Vegetables Subgroup 1C.

PC Code: 06160 I

Decision No.: 483239

Petition No. : 3E820 I DP Barcode: 0415809

Registration No.: None

R eg ulatory Action: Section 3 Registration

Case No

. : 0262 Risk Assessmen t Ty pe: NA

TXR No.: NA CAS No. : 1910-42-5

MRID No.: None 40 CFR: 180.205

From: Thurston G. Morton, Chemist

# ~ 

# »(1 •

A bdallah Khasawinah, Ph.D., Toxicologist 

# /J**{_J.;-..j,~t/~** Ayaa d Assaad, PhD., Toxicologist /

James S. Miller, Environmental Sc ienti st

### ~ .AI(

, Risk Assessment Branch IV**~** Hea lth Effects Division (7509P)

Through: Elissa Reaves Ph.D., Chief

Risk Assessme nt Branch IV

Health Effects Division (7509P)

To: Andrew E rtman

Barbara Madden

Risk Integration, Minor Use & Emerge n cy Response Branch

R egist ration Division (RD) (7505P)

This document provides th e Health Effect s Division's (HED's) risk assessment fo r the Expans ion of Representative Commod it y Use on Potato to Tu berou s and Corm Vegetab l es Subg r oup 1 C.

Page 1 of541.0 EXECUT

- IV

- E SUMMARY

..................... . .................................................... . ..................... 4



### 2.0 HED RECOMMENDATIONS

................................... .. ....................... ..... ... . ..................... 7

2.1 Data Deficiencies/Conditions of Regis t ration

.......................................... . ............. .. ... ... 7

2.2 Tolerance Considerations

................ ................ ......................................... . ..................... 7

2.2.1 Enforcement Analyt ical Method

.. .... .................... .... ......................... . . .. .................. 7

2.2.2 International Harmonization

..... .. .. .............. .. . ........................... . ... .. . . . ..................... 7

2.2.3 Recommended Tolerances

................................. ... .............................. . ......... ..... . .. .... 7

2.2.4 Revisions to Petitioned-For Tolerances

.................................................................. 8



### 3.0 INGREDIEN

- T PROFILE

......... . ...... .. .... ... ................... . ... . ... ..... ... ........... ..... . .. ...... . ............ 8

3.1 Chemical Identity"

.................. . ...... . . ..... ..... .......... ..............•........................

. . ... .. ............... 8

3.2 Physical/Chemica l Characteristics

... .. .. ............. ....................................... . .. .... . ... ... .. ...... 9

3.3 Pesticide Use Pattern

....................................... . ... .. .................. . ................. . .. . ...... ... .. .. ... .. 9

3.3.1 Registered Products

....................... . .................................................... . ..... .. ........... .. . 9

3.3.2 Proposed Nelv Uses

.. .......................................... . ................................ . .................... . 9

3.4 Anticipated Exposure Pathways

...... . ..... .. ...... . ... . ........ ........... .... ...... . . ... . ..................... 9

3.5 Considerations of Environmental Justice

................................................ . .............. ....... 9

4.0 HAZARD CHARACTERIZATION/ASSESSMENT

............................... . ................... 10

4.1 Toxicology Stud ies Available for Anal y sis

.............................................. . ................... 10

4.2 Absorption, Distribution, Metabolism and Excretion

............................ . ................... 10

4.3 Toxicological Effects

........ .. .................. .. . . .................................................. . ....... ....... ..... 10

4.4 Safety Factor for Infants and Children (FQP A Safety" Factor)

............. . ................... 12

4.4.1 Completeness of the Toxicology Database

... . ....................... . ............ . ....... . ........... 12

4.4.2 Evidence of Neurotoxicity"

................................. .. ............................... . ................... 12

4.4.3 Evidence of Sensitivicy/Susceptibilicy in the Developing or Young Animal

..... . 13

4.4.4 Residual Uncerta inty in the Exposure Database

.............................. . ... .. .. . .... ...... . 13

4.5 Toxicity" Endpoint and Point of Departure

......................................... . .... . ................... 13

4.5.1 Dose-Response Assessment

. ..... ... . . . .................................................... . .. .. .. ............. 13

4.5.2 Recommendations for Combining Exposure Routes

......... ...... .. ... .. . . ...... .. ........... 14

4.5.3 Classification of Carcinogenic Potential

............... ...... ...................... . ................... 14

4.5.4 Summary of Points of Departure Used in Risk Assessment

........... . ........ . .......... 14

5.0 DIETARY AND DRINKING WATER EXPOSURE AND RISK ASSESSMENT

.... 16

5.1 Metabolite/Degradate Residue Profi l e

................................................. . ................... 16

5.1.1 Summary of Plant Metabolism Studies

............................................. . ... . ... . ........... 16

5.1.2 Comparison of Metabolic Pathways

.................................................. . ............... .. .. 16

5.1.3 E nvironmental Fate and Transport

.................................................. . ................. .. 16

5.1.4 Residues of Concern Summary and Rationale

...................... ... .. .. .... . ................... 17

5.2 Food Residue Profile

................................................................................. . ................... 17

5.2.1 Residues in Crops

............. .. ...... ..... .. .................................................. .. . .. ....... .. ........ 17

5.3 Water Residue Profile

.. ......................................................... . ....... .. .. .. . .. . . ............ . ... .. 17

5.3.1 Estimated Drinking Water Concentrations

...................................... . .. .. .. .. ...... ... .. 17

Page 2 of 54Page 3 of 54

5.4 Dietary and Drinking Water Exposure and Risk

................................ .................... 18

5.4.1 Acute Dietary and Drinking Water Analysis

................................ ....................... 18

5.4.2 Chronic Dietary and Drinking Water Analysis

................................ ................... 19

6.0 RESIDENTIAL EXPOSURE AND RISK ASSESSMENT

................................ .......... 20

6.1 Residential Bystander Postapplication Inhalation Exposure

................................ .... 20

6.2 Spray Drift

................................ ................................ ................................ ...................... 21

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT

................................ ............ 21

7.1 Short

- , Intermediate

- , and Long

- Term Aggregate Risk

................................ ............ 21

8.0 CUMULATIVE RISK

................................ ................................ ................................ ...... 22

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION

.............................. 22

9.1 Exposure Scenarios

................................ ................................ ................................ ....... 22

9.2 Handler Exposure

................................ ................................ ................................ .......... 22

9.2.1 Handler Exposure Scenarios

................................ ................................ .................. 23

9.2.2 Handler Exposure Data

................................ ................................ .......................... 23

9.2.3 Handler Exposure Assumptions

................................ ................................ ............ 23

9.2.4 Handler Exposure and Risk Estimates

................................ ................................ . 26

9.3 Post Application Exposure

................................ ................................ ............................ 27

9.3.4 Restricted Entry Interval

................................ ................................ ....................... 27

10. REFERENCES

................................ ................................ ................................ .................. 28

APPENDICES

................................ ................................ ................................ ............................. 29

A TOXICOLOGY DAT A SUMMARY

................................ ................................ ............. 29

A.1 Guideline Data Requirements

................................ ................................ .................. 29

A.2 Toxicity Profiles

................................ ................................ ................................ ......... 30

A.3 To xicological Endpoints

................................ ................................ ............................. 34

A.4 EXECUTIVE SUMMARIES

................................ ................................ ................... 38 APPENDIX C. Physical/Chemical Properties

................................ ................................ .......... 54

APPENDIX D. Studies Reviewed for Ethical Conduct

................................ .......................... 54Page 4 of 54

1.0 EXECUTIVE SUMMARY

The Interregional Research Project No. 4 (IR

- 4) , in PP# 3 E 8201 , has proposed the expansion of the potato tolerance for residues of the herbicide paraquat (1,1’

- dimethyl

- 4,4’

- bibyridinium ion) derived from the application of the dichloride salt (calculated as the cation) to Tuberous and Corm Vegetables S ubgroup 1C

.

Use Profile

Paraquat dichloride (hereafter in this document referred to solely as paraquat) is a non

- selective herbicide currently registered for the control of weeds and grasses in agricultural and non

agricultural areas, and for use as a de foliant, desiccant, and plant growth regulator. The Paraquat Reregistration Eligibility Decision (RED) Document (EPA 738

- F

- 96

- 018) was issued in August 1997. The Product and Residue Chemistry Chapters of the RED were completed in July of 1995 (D217262, D . Miller). Currently all registered end

- use products are formulated as paraquat dichloride, and the active ingredient is expressed in terms of the paraquat cation.

Tolerances for residues of paraquat have been established under 40CFR§180.205. The

tolera nces are expressed in terms of residues of paraquat derived from application of either the bis(methyl sulfate) or the dichloride salt (both calculated as the cation). Because there are currently no registered products containing paraquat dimethyl sulfate, the tolerance expression listed under 40CFR§180.205 (a) and §180.205(c) should be revised to remove reference to the bis(methyl sulfate) salt of paraquat.

General tolerances have been established under 40CFR§180.205(a), and range from 0.01 ppm for egg and milk to 210 ppm for Animal feed, non

- grass, group 18, hay. Tolerances with regional registration have been established under 40CFR§180.205(c) at 0.05 ppm for cassava, pigeon pea seed, tanier, tyfon, and true yam, and at 0.1 ppm for taro corm.

The RED Document ( EPA 738

- F

- 96

- 018, 8/97) recommended numerous changes to paraquat tolerances. A Federal Register notice proposing these changes was published on 8/4/ 20 04 (69

FR 47051

- 47068) . The proposed tolerance revisions have not as yet b een finalized.

Proposed New Uses

IR

- 4 has submitted copies of the registered label for a 2.0 lb paraquat cation/gal emulsifiable concentrate ( E C) formulation of paraquat dichloride (Gramoxone SL 2.0 ; EPA Reg. No. 100

- 1431 ). Gramoxone SL 2.0 is proposed for pre plant or pre emergence directed spray to tuberous and corm vegetables subgroup 1C . Maximum application rate is 0. 5 lb a.i./A. A maximum of three applications is proposed. No pre

- harvest interval (PHI) is specified

.

Hazard Identifi cation

The toxicology database for paraquat is considered complete. The primary target organ of paraquat is the lung. Evidence of lung inflammation, scarring, and compromised lung function in response to paraquat are observed throughout the toxicity dat abase in different species (rats, mice, and dogs). Effects in the respiratory tract are observed after acute, subchronic, and chronic exposures regardless of the route of exposure (oral or inhalation). However, inhalation was a

more sensitive route of ex posure than the oral route. With increasing durations of exposure,Page 5 of 54

effects of paraquat in other organ systems are observed. These effects include liver inflammation and necrosis in rats and inflammation and necrosis of the kidneys in rats and mice.

Lent icular changes in the eyes of rats were also observed with increasing durations of exposure. Importantly, the lung effects occur at doses lower than effects in these other organs systems, and so protecting for lung effects protects for all other adverse e ffects of paraquat.

The effects of paraquat in lungs are considered systemic effects. There are no dermal toxicity studies suitable for evaluation of systemic lung effects in the toxicity database for paraquat. Therefore, the Agency is using an oral endpoint for dermal risk assessments with a dermal absorption factor of 0.3%, which was derived from dermal absorption studies conducted in humans and monkeys.

Paraquat did not cause reproductive toxicity. Developmental toxicity in response to paraquat, when observed, always occurred in the presence of maternal toxicity. Four developmental toxicity studies (two in rats and two in mice) are available. If developmental toxicity was present, clear no adverse effect levels were identified which were equival ent to (or exceeded) those for maternal toxicity. Therefore, there was no evidence of quantitative susceptibility. The kinds of developmental effects observed (e.g. reduced body weight/gain and delayed skeletal ossification) are effects that are commonly observed secondary to maternal toxicity. These developmental effects were of lesser severity than those observed in maternal animals (e.g. respiratory distress, reduced body weight, lesions in the lungs and kidneys) demonstrating no evidence of qualitati ve susceptibility in the young.

Previously, the Agency had required that a developmental toxicity study in rabbits be conducted for paraquat. As a result, the FQPA Safety Factor had been retained as a 3X database uncertainty factor for Females 13

- 39 f or the acute dietary risk assessment only. The Agency reviewed the toxicity database for paraquat and concluded that a developmental toxicity study in rabbits was not likely to add information that would impact the paraquat risk assessment (TXR 0056294, A pril 12, 2012). Therefore, this study is no longer required and the FQPA Safety Factor has been reduced to 1X for this population.

No evidence of neurotoxicity was observed in acute and subchronic neurotoxicity studies conducted with paraquat up to the doses at which respiratory effects were observed (e.g. the maximum tolerated dose). There was also no evidence of immunotoxicity in response to

paraquat.

Paraquat was found to be weakly positive in the mouse lymphoma assay and human lymphocyte

cytogen etic assay, and was positive in the sister chromatid exchange assay. Conversely, paraquat was not mutagenic in the Salmonella typhimurium assay, was not genotoxic in the unscheduled DNA synthesis assay in vitro or in vivo , was negative for chromosomal abe rration in the bone marrow test, and no evidence was found for suppressed fertility or dominant lethal mutagenicity in mice. The Cancer Peer Review Committee and the Science Advisory Committee (1989) concluded that there was no evidence of carcinogenicity in animal studies and classified paraquat as a Group E chemical (evidence of non

- carcinogenicity in humans) (TXR

014110 )

.

Paraquat is severely toxic following acute exposure via the dermal and inhalation routes (Category I) and toxic by the oral route of exposure (Category II). It is a dermal and ocular

irritant but is not a skin sensitizer.Page 6 of 54

Dose Response Assessment

Toxicological points of departure (PODs) were selected for dietary/drinking water and occupational exposure scenarios for this assessment. Acute and chronic reference doses (RfDs) were selected for assessment of food and drinking water exposures. The pop ulation adjusted dose (PAD) is equivalent to the reference dose (RfD) divided by the additional FQPA Safety
Factor, which was reduced to 1X for All Populations. An acute RfD/PAD for all populations

was selected from a multi

- generation study in rats which showed increased incidence of alveolar histiocytes in both sexes. A chronic RfD/PAD for all populations was selected from a chronic feeding study in dogs based on increased severity of chronic pneumonitis and gross lung lesions in both sexes and focal pu lmonary granulomas in males. Points of departure for dermal exposures utilized a dermal absorption factor of 0.3% and the same endpoints as those utilized in the dietary assessment, with the multi

- generation study in rats used for short/intermediate

- term dermal assessments and the chronic feeding study in dogs used for long

- term dermal assessments. A subchronic inhalation study in rats was used for short thru long

- term inhalation

assessments. An uncertainty factor of 100x was applied to endpoints selecte d for all exposure routes (10x for interspecies extrapolation, 10x for intraspecies variation)

.

Exposure/Risk Assessment and Risk Characterization

Risk assessments were conducted for dietary (food and water) and occupational exposure pathways based on the proposed expanded use of paraquat on Crop Subgroup 1C

. Paraquat has

no residential uses ; therefore, a residential assessment is not required. Refined acute and chronic dietary and drinking water risk assessments for paraquat showed that dietary and drinking water exposure estimates are below HED’s level of concern for the general population and all population subgroups. Occupational exposure and risk estimates indicate that worker handler and post

- application exposures are not of c oncern at the maximum allowable application rates for the proposed expanded uses. Aggregate risks are not of concern.

Use of Human Studies

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies , listed in Appendix D

, have been determined to require a review of their ethical conduct. Some of these studies are also subject to review by the Human Studies Review Board. All of the studies used have re ceived the appropriate review. Although there are significant gaps in the ethical documentation for these studies, there is no evidence that the research was intended to harm participants or that it was fundamentally unethical in other ways ( MRIDs 00126097, 00126098, & 00126099, K. Sherman, 6/11/2012).Page 7 of 54

2.0 HED RECOMMENDATIONS

2.1 Data Deficiencies/Conditions of Registration

A revised Section F is required.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

PAM Vol. II lists a spectrophotometric method, designated as Method I (LOD = 0.01

- 0.06 ppm),

as being available for the enforcement of tolerances in plant commodities. Several modifications of Method I have been developed for analysis of specific crops, a nd these modified methods

have been used for data collection.

PAM Vol. II lists a spectrophotometric method, designated as Method Ia (LOD = 0.005 ppm), as being available for the enforcement of tolerances in animal commodities. The registrant has submitted descriptions and adequate independent laboratory validation data for a high

performance liquid chromatography method (HPLC; designated as Method 4B) to determine paraquat residues in animal tissues and eggs. The method has been validated by the Analytical Chemistry Branch (ACB). The registrant was requested to make minor changes in the method

write

- up. A revised version of the method has been submitted (RAM 004/04; MRID 43226902) and is now available for enforcement purposes. The reported LOQ is 0.005 ppm for livestock tissues and eggs.

2.2.2 International Harmonization

The Codex Alimentarius Commission has established maximum residue limits (MRLs) for paraquat residues in root and tuber vegetables at 0.05 ppm . The Codex and U.S. tolerances are in harmony with respect to MRL/tolerance expression; both regulate the parent paraquat cation only. The Agency cannot harmonize with the Codex MRL of 0.0 5 ppm since some commodities which the proposed US tolerance is translated from contained residues of > 0.0 5 ppm.

No Canadian or Mexican MRLs have been established for paraquat. Registered food/feed uses of paraquat exist in Canada. These uses presumably fall under the PMRA General MRL of 0.1 mg/kg. Regulation B.15.002(1) of the Canadian Food and Drugs Regulations (FDR) establishes 0.1 ppm as the General Maximum Residue Limit. This regulation states that a food is adulterated if it contains residues of a pesticide at a level greater than 0.1 ppm unless a specific

MRL has been established in Table II, Division 15 of the FDR.

2.2.3 Recommended Tolerances

Pending the submission of a revised Section F, t here are no residue chemistry issues that would preclude granting a registration for paraquat on the Crop Subgroup 1C , as foll ows:

In 2009 HED issued guidance on tolerance expressions (S. Knizner, 2009). We now conclude the tolerance expression should be as follows: Tolerances are established for residues of

paraquat, including its metabolites and degradates, in or on the comm odities in the table below.Page 8 of 54

Compliance with the tolerance levels specified below is to be determined by measuring only paraquat dichloride and calculated as the paraquat cation.

Table 1. Tolerance Summary for Paraquat Dichloride

Commodity Tolerance (ppm) Comments ( correct commodity definition ) Established Proposed Recommended

Tolerances to be established under 40 CFR ' 180.20 5 (a) :

Tuberous and corm vegetables subgroup 1C -- 0. 5 0. 50

Potato 0.5 Revoke Covered by Tuberous and corm vegetables subgroup 1C

Tolerances to be revoked under 40 CFR ' 180.20 5 ( c ) :

Cassava 0.05 Revoke Covered by Tuberous and corm vegetables subgroup 1C

Tanier 0.05 Revoke Covered by Tuberous and corm vegetables subgroup 1C

Yam, true, tuber 0.05 Revoke Covered by Tuberous and corm vegetables subgroup 1C

2.2.4 Revisions to Petitioned

- For Tolerances

The only revisions are for significant figures

.

3 .0 INGREDIENT PROFILE

3.1 Chemical Identity

Table 2. Nomenclature of Paraquat Dichloride.

Compound

Common name Paraquat dichloride

IUPAC name 1,1’

- dimethyl

- 4,4’

- bypyridinium dichloride

CAS name 1,1’

- dimethyl

- 4,4’

- bypyridinium dichloride

CAS registry number 1910

- 42

- 5 (4685

- 14

- 7 for the cation)

End

- use product (EP) 2.0 lb paraquat cation/gal SC (Gramoxone Inteon; EPA Reg. No. 100

- 1217)Page 9 of 54

3.2 Physical/Chemical Characteristics

A table of the physi ochemical properties of paraquat dichloride is provided in Appendix B

. Paraquat dichloride is freely soluble in water, slightly soluble in alcohols, and insoluble in nonpolar organic solvents. It has a very low vapor pressure.

3.3 Pesticide Use Pattern

3.3.1 Registered Products

There are currently 26 active paraquat dichloride registrations including 19 Section 3 registrations and six special local needs (SLNs) or 24(c) registrations and one Experimental Use Permit (EUP)

.

3.3.2 Proposed New Uses

IR

- 4 has submitted a petition (PP# 3 E 8201) for expansion of the use on potato to Crop Subgroup

1C

. The product to be used is Gramoxone SL 2.0 (EPA Reg. No. 100

- 1431 ), an emulsifiable

concentrate ( E C ) formulation which contains 2 lb paraquat cation/gal

. Gramoxone SL 2.0 is proposed for pre plant or preemergence directed spray to tuberous and corm vegetables subgroup 1C. Maximum application rate is 0.5 lb a.i./A. A maximum of three applications is proposed. No pre

- harvest interval (PHI) is specified.

3.4 Anticipated Exposure Pathways

Dietary (food and water) exposures are expected based on existing uses of paraquat dichloride

and the requested expanded uses . A residential exposure assessment is not required for this

assessment because there are no residential uses or exposures associa ted with paraquat
dichloride

.

3.5 Considerations of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "F ederal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," http://www.eh.doe.gov/oepa/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 pesticide exposures that are based on pat terns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for ad ult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development, as OPP has committed resources and expertise to the development of specialized so ftware and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.Page 10 of 54

4 .0 HAZARD CHARACTERIZATION/ASSESSMENT

4.1 Toxicology Studies Available for Analysis

T he toxicology database for paraquat dichloride is considered complete. Acute and subchronic neurotoxicity studies required by the new 40 CFR Part 158 data requirements have been submitted and reviewed by the Agency

. An immunotoxicity study that was also a new data

re quirement has been submitted , been reviewed and acceptable. None of these recently submitted studies alter the endpoints selected for this risk assessment.

 Acute: Oral, dermal, inhalation, eye irritation, dermal irritation, and skin sensitization

 Subchronic: 90

- day oral toxicity ( dog ), 21

- day dermal toxicity (rabbit) , 21

- day inhalation

 Developmental toxicity : developmental toxicity (rat and mouse ; rabbit study was

waived )

 Reproduction: 3

- generation reproduction (rat)

 Chronic: combined oral chronic toxicity/carcinogenicity (rat), carcinogenicity (mouse), chronic oral toxicity (dog)

 Neurotoxicity: Acute and Subchronic neurotoxicity (rat),

 Other: mutagenicity battery, metabolism, immunotoxicity (mouse)

, in vivo human dermal absorption

4.2 Absorpti on, Distribution, Metabolism and Excretion

Paraquat is poorly abso rbed after oral administration to rats, dogs and mice

. After oral administration (gastric intubation) of single doses of paraquat dichloride or dimethylsulfate to

Wistar strain male and fe male rats, most of the administered radioactivity (69

- 96%) was excreted

in feces as unchanged parent (e.g. was not metabolized). Of the fraction that was metabolized (up to 30%) the route of degradation was found to be microbial degradation of paraquat i n the gut. Most of the administered dose of paraquat is excreted in the feces within 2

- 3 days. The excretion profile of paraquat changed markedly with the route of administration. After

subcutane ous injection , unchanged paraquat appeared mostly in uri ne (73

- 96% of the administered radioactivity), where it was excreted as unchanged parent (73

- 96% dose) within 1 day o f dosing.

The fraction of paraquat that is orally absorbed was rapidly distributed to most tissues (particularly the lungs and kidneys). Tissues other than the lungs d id not retain paraquat.

4.3 Toxicological Effects

The primary target organ of paraquat is the lung. Evidence of lung inflammation, scarring, and compromised lung function in response to paraquat are observed throughout t he toxicity database in different species (rats, mice, and dogs). Effects in the respiratory tract are observed after acute, subchronic, and chronic exposures regardless of the route of exposure (oral or inhalation). However, inhalation was a more sensi tive route of exposure than the oral route. With increasing durations of exposure, effects of paraquat in other organ systems are observed. These effects include liver inflammation and necrosis in rats and inflammation and necrosis of the kidneys in

rat s and mice. Lenticular changes in the eyes of rats were also observed with increasing durations of exposure. Importantly, the lung effects occur at doses lower than effects in thesePage 11 of 54

other organs systems, and so protecting for lung effects protects for al l other adverse effects of

paraquat.

The effects of paraquat in lungs are considered systemic effects. There are no dermal toxicity studies suitable for evaluation of systemic lung effects in the toxicity database for paraquat. The only available dermal toxicity study was conducted in rabbits. Since severe skin damage resulted at relatively low topical doses (6 mg/kg), it was not possible to test doses high enough to result in systemic toxicity, particularly lung effects. Therefore, the Agency i s using a dermal absorption factor of 0.3% that was derived from dermal absorption studies conducted with paraquat in humans (MRID 00153439) and an oral endpoint for dermal risk assessments

Paraquat did not cause reproductive toxicity. Developmental to xicity in response to paraquat, when observed, always occurred in the presence of maternal toxicity. Four developmental toxicity studies (two in rats and two in mice) are available. If developmental toxicity was present, clear no adverse effect levels we re identified which were equivalent to (or exceeded) those for maternal toxicity. Therefore, there was no evidence of quantitative susceptibility. The kinds of developmental effects observed (e.g. reduced body weight/gain and delayed skeletal

ossificatio n) are effects that are commonly observed secondary to maternal toxicity. These developmental effects were of lesser severity than those observed in maternal animals (e.g. respiratory distress, reduced body weight, lesions in the lungs and kidneys) demons trating no evidence of qualitative susceptibility in the young.

Previously, the Agency had required that a developmental toxicity study in rabbits be conducted for paraquat. As a result, the FQPA Safety Factor had been retained as a 3X database

uncert ainty factor for Females 13

- 39 the acute dietary risk assessment only. The Agency reviewed the toxicity database for paraquat and concluded that a developmental toxicity study in rabbits was not likely to add information that would impact the paraquat ris k assessment (TXR 0056294, April 12, 2012). Therefore, this study is no longer required and the FQPA Safety Factor has been reduced to 1X for this population.

No evidence of neurotoxicity was observed in acute and subchronic neurotoxicity studies

condu cted with paraquat up to the doses at which respiratory effects were observed (e.g. the maximum tolerated dose). There was also no evidence of immunotoxicity in response to

paraquat.

Paraquat was found to be weakly positive in the mouse lymphoma assay and human lymphocyte cytogenetic assay, and was positive in the sister chromatid exchange assay. Conversely, paraquat was not mutagenic in the Salmonella typhimurium assay, was not genotoxic in the unscheduled DNA synthesis assay in vitro or in vivo , was negative for chromosomal aberration in the bone marrow test, and no evidence was found for suppressed fertility or dominant lethal mutagenicity in mice. The Cancer Peer Review Committee and the Science Advisory Committee (1989) concluded that there was no evidence of carcinogenicity in animal studies and classified paraquat as a Group E chemical (evidence of non

- carcinogenicity in humans).

Paraquat is severely toxic following acute exposure via the dermal and inhalation routes (Category I) and is toxic by the oral route of exposure (Category II). It is a dermal and ocular

irritant but is not a skin sensitizer.

The complete toxicity profile for paraquat is provided in Appendix A.Page 12 of 54

4.4 S afety Factor for Infants and Children (FQPA Safety Factor)

The toxicological database for paraquat is complete. Previously, the Agency had required that a developmental toxicity study in rabbits be conducted for paraquat. As a result, the FQPA Safety Factor had been retained as a 3X database uncertainty factor for Females 13

- 39 the acute dietary

risk assessment. T he Agency recently reviewed the toxicity database for paraquat and concluded that a developmental toxicity study in rabbits was not likely to add information that would impact the paraquat risk assessment (TXR 0056294)

. Therefore, this study is no longer required and the FQPA Safety Factor has been reduced to 1X for this population for the acute dietary risk

assessment.

The FQPA Safety Factor remains reduced to 1X for the acute dietary assessment for the General Population and also remains reduced to 1X for the chronic dietary assessment for All Populations. Reduction of the FQPA Safety Factor to 1X is supported by:

 No evidence of neurotoxicity in the toxicity database;

 No indication of quantitative or qualitative susceptibility of mice or rats to in utero and/or

pre

- or post

- natal exposure in five studies investigating these parameters;

 Clear NOAELs for developmental e ffects, when observed;

 A conservative dietary assessments that does not underestimate the potential exposures for infants and children;

 No registered or proposed residential uses for paraquat.

4.4.1 Completeness of the Toxicology Database

The toxicity d atabase for paraquat is considered complete. Previously, the Agency had required that a developmental toxicity study in rabbits be conducted for paraquat in order to fully satisfy Part 158 data requirements. The Agency recently reviewed the toxicity dat abase for paraquat and concluded that a developmental toxicity study in rabbits was not likely to add information that would impact the paraquat risk assessment (TXR 0056294 ). There are five studies available in which to assess the effects of paraquat on development. There are two developmental toxicity studies conducted in rats; two developmental toxicity studies conducted in mice, and a 3

- generation reproductive and developmental toxicity study conducted in rats. Guideline acute

and subchronic neuroto xicity studies are also available.

4.4.2 Evidence of Neurotoxicity

Guideline acute and subchronic neurotoxicity studies in adult rats were performed that included functional observational batteries for neurological effects and detailed histopathology of the nervous system. No evidence of neurotoxicity was observed in the se studies at dose levels up to those that cause respiratory distress and death. Also, paraquat did not cause neurotoxic effects in any of the other studies in the toxicity database. The Agency has low concern for paraquat to be a developmental neurotoxi cant due to an absence of neurotoxic effects in the Agency’s toxicity database, together with developmental toxicity studies indicating that fetal toxicity is secondary to maternal toxicity. Due to this low concern, a developmental neurotoxicity study is not required.Page 13 of 54

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

Developmental toxicity in response to paraquat, when observed, always occurred in the presence of maternal toxicity. Four developmental toxicity studies (two in rats and two in mice) and a 3

- generation reproduction toxicity study are available. Developme ntal toxicity was observed in one developmental rat study and one developmental mouse study and always occurred in the context of severe maternal toxicity (e.g. respiratory distress, reduced body weight, lesions in the lungs and kidneys). There was no qu antitative susceptibility, since developmental effects were observed at the same dose that caused maternal toxicity. The kinds of developmental effects observed in these studies (e.g. reduced body weight/gain and delayed skeletal ossification) are

effects that are commonly observed secondary to maternal toxicity, and clear NOAELs for developmental effects were always identified. Since effects in the offspring, when present, were lesser in severity than those observed in maternal animals and were also cons istent with those commonly observed as secondary to maternal toxicity, the Agency has concluded that there was no evidence of qualitative susceptibility in the young to paraquat.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. The dietary risk assessment is conservative and will not underestimate dietary and/or non

- dietary residential exposure to paraquat dichloride.

4.5 Toxicity Endpoint and Point of Departure

4.5.1 Dose

- Response Assessment

Toxicity endpoints and points of departure (PODs) for dietary (food and water) and occupational scenarios are summarized below. A detailed description of the studies used as a basis for the

selected end points are presented in Appendix A.

Toxicological points of departure (PODs) were selected for dietary/drinking water and occupational exposure scenarios for this assessment. Acute and chronic reference doses (RfDs)

were selected for assessment of food and drinking water exposures. The population adjusted dose (PAD) is equivalent to the reference dose (RfD) divided by the additional FQPA Safety
Factor, which was reduced to 1X for All Populations. An acute RfD/PAD for all populations

was selected from a multi

- generation study in rats which showed increased incidence of alveolar histiocytes in both sexes. A chronic RfD/PAD for all populations was selected from a chronic feeding study in dogs based on increased severity of chronic pneumonitis and gross lung lesions in both sexes and focal pulmonary granulomas in males. Points of departure for dermal exposures utilized a dermal absorption factor of 0.3% and the same endpoints as those utilized in the dietary assessment, with the multi

- generation study i n rats used for short/intermediate

- term dermal assessments and the chronic feeding study in dogs used for long

- term dermal assessments. A subchronic inhalation study in rats was used for short thru long

- term inhalation

assessments. An uncertainty factor of 100x was applied to endpoints selected for all exposure routes (10x for interspecies extrapolation, 10x for intraspecies variation).Page 14 of 54

4.5.2 Recommendations for Combining Exposure Routes

The acute and chronic aggregate exposure assessments for all population subgroups include only food and water exposures. T here are currently no residential uses for paraquat and there are no

short

- or intermediate

- term exposure scenarios. Therefore, non

- occupational short

- and

intermediate

- term aggregate risk assessments were not conducted

.

For occupational assessments, the toxic endpoint of concern (e.g. lung effects) is the same for both inhalation and dermal routes of exposure. Therefore, these route s should be aggregated when assessing worker risks.

4.5.3 Classification of Carcinogenic Potential

Paraquat is currently placed in Category E (evidence of non

- carcinogenicity to humans). The

carc inogenic potential of paraquat was evaluated by the Toxicology Branch Peer Review Committee (now Carcinogenicity Assessment Review Committee (CARC) ) in 1986, 1988, and 1989, and by the Scientific Advisory Panel (SAP) in 1989. In 1986 the CARC classified

p araquat as a Category C carcinogen (limited evidence of carcinogenicity in animals), based on an apparent increase in erroneously combined squamous cell carcinomas in different locations in the head region. In F ebruary of 1989 the SAP classified paraquat as Category D (equivocal evidence of carcinogenicity) based on squamous cell carcinoma in the nasal cavity of 2 high

dose rats. However, the SAP also commented that endpoints other than carcinogenicity were more relevant for the regulation of paraquat. F inally, in the following month (March of 1989) the CARC placed paraquat in Category E (as it had done the previous year, 1988). As a result, for this human health risk assessment, paraquat is classified in Category E, i.e., there is evidence

of non

- carcin ogenicity to humans (TXR 0 014110 ).

Paraquat was found to be weakly positive in the mouse lymphoma assay and human lymphocyte cytogenetic assay and was positive for sister chromatid exchange assay. Conversely, paraquat was not mutagenic in the Salmonella typhimurium assay, not genotoxic in the unscheduled DNA synthesis assay in vivo or in vitro , negative for chromosomal aberration in the bone marrow test

, and no evidence was found for suppressed fertility or domin ant lethal mutagenicity in mice

.

4.5.4 Summary of Points of Departure Used in Risk Assessment

Toxicological doses/endpoints selected for the paraquat risk assessment are provided in Table 3.Page 15 of 54

Table 3 . Summary of Toxicological Doses and Endpoints for Paraquat for Use in Human Health Risk

Assessments

Exposure

Scenario Dose Used in Risk

Assessment, UF Special FQPA SF and

Level of Concern for

Risk Assessment Study and Toxicological Effects

Acute Dietary ( all population s ) NOAEL = 1.25

mg/kg/day

UF = 100

Acute RfD = 0.0125 mg/kg/day FQPA SF = 1x

aPAD = 0.0125 mg/kg/day Multi

- generation rat study

MRID 00126783, 00149748, and

00149749 LOAEL = 3.75 mg/kg/day, based on

increased incidences of alveolar histiocytes in both sexes

Chronic Dietary (all populations) NOAEL = 0.45

mg/kg/day

UF = 100

Chronic RfD = 0.0045 mg/kg/day FQPA SF = 1x

cPAD = 0.0045 mg/kg/day Chronic toxicity in dogs

MRID 00132472 LOAEL = 0.93 mg/kg/day, based on increased severity of chronic pneumonitis and gross lung lesions in both sexes, and focal pulmonary

granu lomas in males

Dermal

Short

- - Intermediate

- Term (1day

– 6 months) NOAEL = 1.25

mg/kg/day LOC = MOE = 100

Dermal absorption

factor = 0.3% Multi

- generation rat study

MRID 00126783, 00149748, and

00149749 LOAEL = 3.75 mg/kg/day, based on

increased incidences of alveolar histiocytes in both sexes

Dermal Long

- Term (> 6 months) NOAEL = 0.45

mg/kg/day LOC = MOE = 100

Dermal absorption

factor = 0.3% Chronic toxicity in dogs

MRID 00132472 LOAEL = 0.93 mg/kg/day, based on increased severity of chronic pneumonitis and gross lung lesions in both sexes, and focal pulmonary granulomas in males

Inhalation

Short

- through Long

- Term (1 day

- > 6 months) NOAEL = 0.01

μ g/L for respirable particles

NOAEL = 1.25 mg/kg/day for non

respirable particles LOC = MOE = 100

Inhalation absorption

factor = 100% 21

- Day inhalation toxicity study in rats (respirable particles)

MRID 00113718

LOAEL = 0.10 μ g/L, based on squamous keratinizing metaplasia and hyperplasia of the epithelium of the larynx

3

- generation reproduction study (non

respirable particles)

MRID 00126783, 00149748, and

00149749

Cancer (oral, dermal, inhalation) Classification: Category E (evidence of non

- carcinogenicity to humans) (TXR 0 014110)

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 ApplicablePage 16 of 54

5.0 DIETARY AND DRINKING WATER EXPOSURE AND RISK ASSESSMENT

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant Metabolism Studies

The r esidue c hemistry c hapter of the paraquat RED (D217262, D. Miller, 7/28/95) concluded that, f or the purposes of reregistration and risk assessment, the qualitative nature of the residue in plants is adequately understood based on studies depicting the metabolism of paraquat in carrots and lettuce following preemergence treatment and in pot atoes and soybeans following desiccant treatment. The residue of concern in plants is parent paraquat.

5.1.2 Comparison of Metabolic Pathways

Paraquat is very stable. In both primary crops and rotational crops, parent paraquat was the only major residue. In goats, pigs, and poultry, paraquat was again the only residue of concern. Paraquat was not metabolized by rats. Paraquat was poorly absorbed after oral administration to rats, dogs and mice. Once absorbed, paraquat was rapidly distributed to most tissues but especially to lungs and kidneys. Tissues other than lungs did not retain paraquat. In the environment, paraquat is very persistent and undergoes minimal degradation. As a result of the findings of the plant and animal metabolism studie s as well as the environmental degradation studies, parent paraquat is the only residue of concern considered in this human health risk

assessment.

5.1.3 Environmental Fate and Transport

Paraquat undergoes minimal degrad ation in the environment, and thus is very persistent (as parent). However, its very high propensity to bind to solids, particularly clay, makes it very immobile. In addition, paraquat does not readily appear to desorb from clay. The greatest cause

for conce rn is likely to be erosion of contaminated sediments off

- site and subsequent re

deposition onto non

- target areas (especially surface water bodies). There is an additional (minor) concern for the one proposed new usage ( w heat) that includes aerial spray; however, this use entails very small amounts (relative to all other uses), so spray drift onto nearby surface water drinking water sources should be fairly limited. Because of i ts very low mobility and strong tendency to bind tightly to soils, paraquat contamination of drinking water supplies derived from groundwater is expected to be highly unlikely. In addition, the strong binding characteristics of paraquat are likely to render most residues in raw drinking water sourc es removable through sedimentation processes, which are typically included as part of standard drinking water

treatments.Page 17 of 54

5.1. 4 Residues of Concern Summary and Rationale

T he residue chemistry chapter of the RED (D217262, D. Miller, 7/28/95) conclu ded that f or purposes of reregistration and risk assessment, the qualitative nature of the residue in plants and livestock is adequately understood based on the combined results of metabolism studies. The residue of concern is parent paraquat.

Table 5.1. 4 provides a summary of the MARC decisions regarding residues of concern for

paraquat

.

Table 5.1. 4 . 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 Parent Paraquat Parent Paraquat

Rotational Crop Parent Paraquat Parent Paraquat

Livestock Ruminant Parent Paraquat Parent Paraquat

Poultry Parent Paraquat Parent Paraquat

Drinking Water Parent Paraquat N/A

5.2 Food Residue Profile

5.2.1 Residues in Crops

No residue field trial data have been submitted for this petition. An expansion from the potato tolerance to Crop subgroup 1C was requested

. Potato is the representative crop for Crop subgroup 1C and adequate field trial date has been previously been submitted. T herefore, no additional residue data are required.

5.3 Water Residue Profile

5.3. 1 Estimated Drinking Water Concentrations

The drinking water estimates used in the dietary risk assessment were provided by the Environmental Fate and Effects Division (EFED; Memo, J. Lin, 10

- January

- 2012; D396402).

EFED reviewed a non

- guideline supplemental mobility study (MRID 48659501) . The s ubmitted study was conducted to evaluate the effects of traditional water treatment processes on paraquat and to determine the mobility of paraquat through soil filtration column. This memorandum only addresses the first aspect on the effects of using jar tests as a mean to mimic traditional water treatment processes to determine whether the results of jar tests are sufficient to provide the justification to refine the previous drinking water assessment (J. Lin, 11

- May

- 2011; D381972).Page 18 of 54

14 C

- paraquat, spiked at ~30 ppb into the raw surface water samples from five representative US CWS (community water supply) facilities, was effectively removed by a combination of typical water treatment processes conducted on a laboratory

- scale: the “laboratory jar test” (co agulation using alum with either lime or soda ash, flocculation and sedimentation), followed by duel media filtration (anthracite atop of filtering sand). The combination process was able to reduce the

level of 14 C

- paraquat to approximate or below the lim it of detection of about 0.15μg/L (ppb). The jar test results allow EFED to better characterize potential levels in finished water for drinking water assessment purpose. The level of paraquat in the finish ed water of 0.15 μg/L

should be used for the drink ing water assessment.

5

. 4 Dietary and Drinking Water Exposure and Risk

Refined acute and chronic dietary and drinking water exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model with the Food Commodity Intake Database (DEEM

- FCIDTM). Dietary risk assessment incorporates both exposure and toxicity of a given pesticide. For acute and chronic dietary assessments, the risk is expressed as a percentage of a maximum acceptable dose (i.e., the dose which HED has concluded will result in no unreasonable adverse health effects). This dose is referred to as t he population adjusted dose (PAD). The PAD is equivalent to the reference dose (RfD) divided by the additional Safety Factor, if applied. For acute and non

- cancer chronic exposures, HED is concerned when estimated dietary risk exceeds 100% of the PAD.

5

. 4 .1 Acute Dietary and Drinking Water Analysis

A refined (probabilistic) acute dietary exposure analysis was performed for the general population and all population subgroup s

. The acute analysis assumed a distribution of residues

based on tolerance level residues . Empirical and DEEM default processing factors were used to modify the field trial data. M aximum screening

- level percent crop treated estimates were used

for commodities for which data were available. If no percent crop treated data were available, 100% crop treated was assumed. The acute analysis incorporated the jar test result concentration of 0.15 ppb for the drinking water residue

. Acute dietary risk estimates are not of concern for general population or other population subgroups. The subgroup with the highest risk estimate

was children 1.2 years old with a 99.9 th percentile acute exposure estimate of 7 5 % of the aPAD.

The 99.9 th percentile aPAD for the general U.S. population was 31 %.Pag e 19 of 54 Table 5 .4.1 . Results of Acute Dietary Exposure Analysis for Paraquat (Food and Drinking Water)

Population Subgroup aPAD (mkd)* 99.9 th Percentile

Exposure (mkd) % aPAD

General U.S. Population 0.0125 0.003932 31

All Infants (< 1 year old) 0.0125 0.00 8424 67

Children 1

- 2 years old 0.0125 0.00 9345 75

Children 3

- 5 years old 0.0125 0.004594 37

Children 6

- 12 years old 0.0125 0.003302 26

Youth 13

- 19 years old 0.0125 0.002026 16

Adults 20

- 49 years old 0.0125 0.002108 17

Adults 50+ years old 0.0125 0.002095 17

Females 13

- 49 years old 0.0042 0.002060 16

*mkd: milligram per kilogram per day

5

. 4 .2 Chronic Dietary and Drinking Water Analysis

A conservative chronic dietary exposure analysis was performed for the general U.S. population and various population subgroups. Tolerance level residues and average percent crop treated assumptions were used. DEEM default and empirical processing factor s were used to modify the

tolerance values. The chronic analysis incorporated the jar test result concentration of 0.15 ppb for the drinking water residue. Chronic dietary risk estimates are not of concern for general population or other population subgr oups. The subgroup with the highest risk estimate w ere children 1

- 2 years old with a cPAD of 27 %. The % cPAD for the general U.S. population was

7. 1 %.Pag e 20 of 54 Table 5.4.2 . Results of Chronic Dietary Exposure Analysis for Paraquat (Food and Drinking Water)

Population Subgroup c PAD (mkd)* Exposure (mkd) % aPAD

General U.S. Population

0.0 045 0.000321 7.1

All Infants (< 1 year old) 0.00 0833 19

Children 1

- 2 years old 0.00 1215 27

Children 3

- 5 years old 0.000819 18

Children 6

- 12 years old 0.000480 11

Youth 13

- 19 years old 0.000257 5.7

Adults 20

- 49 years old 0.000236 5.2

Adults 50+ years old 0.000233 5.2

Females 13

- 49 years old 0.000222 4.9

*mkd: milligram per kilogram per day

6 .0 RESIDENTIAL EXPOSURE AND RISK ASSESSMENT

Residential exposures and risk are not assessed in this document because the proposed uses of paraquat do not involve applications by homeowners or commercial applicators in residential settings at this time and there are no existing residentia l uses.

6.1 Residential Bystander Postapplication Inhalation Exposure

There are no residential uses proposed for paraquat in this registration action, therefore a residential exposure assessment was not conducted.

Based on the Agency's current practi ces, a quantitative post

- application inhalation exposure assessment was not performed for paraquat at this time primarily because of low vapor pressure (<10

- 7 ), and the low proposed use rate (0.50 lb ai/A). However, volatilization of pesticides may

be a s ource of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 1 . The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post

- application inhalation exposure assessment for paraquat.

1 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlPag e 21 of 54

6.2 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom) employed for paraquat

. The Agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call

- In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information). 2 The Agency is also taking means to qualitatively and qualitatively addre ss spray drift as a potential source of exposure in risk assessments for pesticides through existing programs such as Ag Drift and chemical specific properties of pesticides. The potential for spray drift will be quantitatively evaluated for each pesticid e during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently.

Although a quantitative residential post

- application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers. This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post

- application inhalation exposure scenarios

.

7 .0 AGGREGATE EXPOSURE AND RISK ASSESSMENT

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

HED consider s both the route and duration of exposure. Since there are no residential uses of paraquat the a cute and chronic aggregate exposures include food plus drinking water exposures. Acute and chronic aggregate risks are not of concern.

7 .1 Short

- , Intermed iate

- , and Long

- Term Aggregate Risk

There are no current or proposed residential uses of paraquat. Therefore, the acute and chronic exposure estimates provided in the dietary and drinking water exposure section represent

aggregate exposure.

2 Available: http://www.epa.gov/opp00001/fac tsheets/spraydrift.htmPag e 22 of 54

8.0 CUMULATIVE RISK

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider “available information” concerning the cumulative effects of a particular pesticide's residues and “other substances that have a common mechanism of toxicity.”

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 paraquat and any other substances, and paraquat 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 paraquat 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 CHARACTERIZATION

9 .1 Exposure Scenarios

Occupational handler and post

- application exposure scenarios were assessed for the proposed use of paraquat on perennial tropical and sub

- tropical fruit trees. Based on the product labels and information provided by the registrant, short

- and intermediate

- term exposure is assessed for occupational handlers and post

- application activities. Dermal and inhalation exposures to workers are aggregated for paraquat because the toxicity endpoints for these exposure routes are based on common toxicological effects

.

9

. 2 Handler Exposure

The term “handler” applies to individuals who mix, load, and apply the pesticide product. The following handler exposure scenarios were assessed for the proposed expanded uses.Pag e 23 of 54

9.2.1 Handler Exposure Scenarios

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupatio nal handlers is based on the following scenarios:

MIXER/LOADER

1. Open mixing/loading for groundboom and aerial applications.

APPLICATORS

1. Applying sprays with groundboom and aerial equipment.

FLAGGERS

1. Aerial applications

9.2.2 Handler Exposure Data

No chemical

- specific handler exposure data were submitted in support of this registration It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical

- specific data, include PHED 1.1, the AHETF database, the Outdoor Residential Exposure Task Force (ORETF) database, or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate

Reference Tabl e 3 ”, which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website 4

.

9.2. 3 Handler Exposure Assumptions

Unit Exposures It is the policy of HED to use the best available data to assess handler exposure. In the case of paraquat, chemical

- specific applicator exposure monitoring data were submitted to the Agency in support of the occupational handler assessment for the Paraqu at Dichloride RED. For details concerning this data, see memorandums T. Manville, July 1996, D224830, D227710 and the Re

registration Eligibility Decision (RED) (August 1997). In these previous assessments, a bio

monitoring study [(MRID: 436442

- 02), 1995 . D. Meier. Paraquat: Worker Exposure during Mixing, Loading, and Application of GRAMOXONE® EXTRA to Pecans Using Vehicle

Mounted Ground Boom Equipment] was used for assessing aerial and groundboom exposure scenarios. However, not all participants in th e study adhered to label specific PPE; therefore, this study was not used in this current assessment, and instead generic handler data were used as surrogate data.

3 Available: http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf

4 Available: http://www.epa.gov/pesticides/science/handler

- exposure

- data.htmlPag e 24 of 54

Sources of generic handler data, used as surrogate data in the absence of chemical

- specif ic data, include PHED 1.1, the AHETF database, the Outdoor Residential Exposure Task Force (ORETF) database, or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protec tion provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table 5 ”, wh ich, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website 6

.

Area/Amount Treated Based on HED ExpoSAC Policy No. 9.1, the area treated in a day was assu med to be:

 1200 acres for mixing/loading to support aerial applications.

 1200 acres for applying to support aerial applications.

 200 acres for mixing/loading to support groundboom applications,

 200 acres for applying with groundboom equipment.

 350 acres fo r flaggers.

Application Rate For the purpose of this registration action, SyngentaTM has submitted copies of the registered label for a 2.0 lb paraquat cation/gal soluble concentrate (SL) formulation of paraquat dichloride (Gramoxone 2.0; EPA Reg. No. 100

- 1431). Gramoxone 2.0 is proposed for post

- emergence ground directed spray to previously planted crop group 1C . The maximum application rates are (2.0 pints/A) 0.50 lb a.i./A for groundboom and aerial applications, however in California, Wahsington, Oreg on, and Idaho, A maximum of 3 applications is proposed along with a 14

- day

pre

- harvest interval (PHI).

Body Weight The average adult body weight of 80 kg was used for estimating short

- term dermal and inhalation daily dose calculations.

Absorption Factor s Since the short

- and intermediate

- term dermal PoD was based on a 21 day inhalation study, therefore a 0.3% dermal absorption factor was used to estimate dermal exposure, and 100% absorption was assumed for estimating inhalation exposure.

Equations and Calculations

Daily Dose: Daily dose (dermal and inhalation) is calculated by normalizing the daily exposure (dermal or inhalation) value by body weight and accounting for absorption factors:

Average Daily Dose ( mg kg / day ) = Daily Exposure ( mg ai day ) x Absorption Factor ⁄

Body Weig h t ( kg ) ⁄

5 Available: http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf

6 Available: http://www.epa.gov/pesticides/science/handler

- exposure

- data.htmlPag e 25 of 54

Where: Average Daily Dose = Absorbed dose received from exposure to a pesticide in a given

scenario (mg pesticide active ingredient/kg body weight/day),

Daily Exposure = Amount (mg ai/day) deposited on the surface of the skin that is

available for dermal absorption or amount inhaled that is available for inhalation absorption,

Absorption Factor = A measure of the amount of chemical that crosses a biological

boundary such as the skin or lungs, and

Body Weight = Body weight determined to represent the population of interest in a risk

assessment.

Margin of Exposure (MOE): The daily dermal and inhalation dose received by occu pational handlers was compared to the appropriate PoD (i.e. NOAELs) to assess the risk to occupational handlers. All MOE values were calculated using the following formula:

MOE = NOAEL ( ( mg / kg / day )

Average Daily Dose ( mg / k g / day )

Where:

MOE = Margin of exposure value used by HED to represent risk or how close

a chemical exposure is to being a concern (unitless),

ADD = A verage daily dose (ADD) is absorbed dose received from exposure to

pesticide, and

NOAEL = Dose level in a toxicity study, where no observed adverse effects occurred in

the study.

Combined Risk Estimates

Dermal and inhalation risk estimates were combined in this assessment, since the toxicological effects for these exposure routes were simil ar. Dermal and inhalation risk estimates were combined using the following formula:

Total MOE = Point of Departure ( mg / kg / day )

Combined dermal + in h alation dose ( mg / kg / day )Pag e 26 of 54

9.2. 4 Handler Exposure and Risk Estimates

For all short

- and intermediate

- term risk estimates for occupational handlers, there are no risk estimates of concern (MOE ≥ 100). MOEs, ranged from 190 (aerial mixing and loading/baseline) to 8,800 for (groundboom “open cab” baseline with gloves). See tab le 9.2 .4 for details.

Table 9.2.4 : Occupational Short and Intermediate

- Term Risk Assessment Uses of Paraquat

Exposure

Scenario Crops Application.

Rate Area

Treated Inhalation

Unit Exp. Dermal

Unit Exp. Inhalation

Daily Dose Dermal

Daily Dose Combined MOE 5

Short/Int

- term

(lb a.i/A) 1 (A/day) 2 (  g/lb ai) 3 (  g/lb ai) 3 (mg/kg/day)

4 (mg/kg/day)

4 (Dermal+

Inhalation)

Mixer/Loader (soluble concentrate)

Aerial

Crop

Group (1C) 0.50 1200 0.22 (baseline) 220

(baseline) 0.0016 0.0049 Baseline = 190

0.0438 (label PPE 6 ) 37.6

(label PPE 6 ) 0.00033 0.00085 Baseline/Gloves/ PF5 = 1,100

Groundboom 200 0.22 (baseline) 220

(baseline) 0.00027 0.00083 Baseline = 1,100

0.0438 (label PPE 6 ) 37.6

(label PPE 6 ) 0.000055 0.00014 Baseline/Gloves/
PF5 = 6,400

Applying ( soluble concentrate)

Groundboom (Open Cab) Crop

Group (1C) 0.50 200 0.34 (baseline) 78.6

(baseline) 0.00043 0.00030 Baseline = 1,700

0.068 (label PPE 6 ) 16.1

(label PPE 6 ) 0.000085 0.000060 Baseline/Gloves/
PF5= 8,800

Flagger

Aerial Crop

Group (1C) 0.50 350 0.35 (no respirator) 11

(baseline) 0.000766 0.0000724 Baseline = 1,500

1. Application rates are based on maximum values found in proposed labels: Gramoxone 2.0 ®; (EPA Registration Number 100

- 1431) 2. Daily area treated is based on ExpoSAC Policy 9. 3. HED policies on use of surrogate data, including their sources, are presented in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( http://www.epa.gov/pesticides/science/handler

- exposure

- table.pdf ) and (http://www.epa.gov/pesticides/science/handler

- exposure

data.html) 4. Daily Dose (mg/kg/day) was calculated by: [(Unit Exposure * Absorption factor * Appl. rate * Area treated) / 80 kg].

5. Short

- /Intermediate

- Term Combined MOE = Dermal + Inhalation. Shor t and Intermediate

- term endpoints are the same [(NOAEL 1.25 mg/kg/day)], thus one column. The LOC for the target MOE = 100. 6. Label PPE = single layer of work clothing consisting of a long sleeved shirt, long pants, shoes, plus socks, chemical resi stant gloves, protective eyewear, and a dust mist NIOSH approved respirator (N, R, P, or HE filter)

Note:

 For Aerial applicator, the groundboom applicator exposure scenario is protective.Pag e 27 of 54

The Agency matches quantitative occupational exposure assessment with appropriate characterization of exposure potential. While HED presents quantitative risk estimates for human flaggers where appropriate, agricultural aviation has changed dramatically over the past two decades. According the 2012 National Agricultural Avia tion Association (NAAA) survey of their membership, the use of GPS for swath guidance in agricultural aviation has grown steadily from the mid 1990’s. Over the same time period, the use of human flaggers for aerial pesticide applications has decreased stea dily from ~15% in the late 1990’s to only 1% in the most recent (2012) NAAA survey. The Agency will continue to monitor all available information sources to best assess and characterize the exposure potential for human flaggers in agricultural aerial appli cations.

HED has no data to assess exposures to pilots using open cockpits. The only data available is for exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the engineering control (enclosed cockpits) and baseline at tire (long

- sleeve shirt, long pants, shoes, and socks); per the Agency’s Worker Protection Standard stipulations for engineering controls, pilots are not required to wear protective gloves for the duration of the application. With this level of protection , there are no risk estimates of concern for applicators.

9.3 Post Application Exposure

HED uses the term post

- application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post

- application exposure le vels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications,

rela tive to harvest activities, can greatly reduce the potential for post

- application exposure.

For this registration action, no post

- application assessment was conducted, whereas the application is a pre

- emergent ground directed activity. No quantitative wor ker exposure is expected.

9.3. 4 Restricted Entry Interval

The REI specified on the proposed label is based on the acute toxicity of paraquat. Paraquat is classified as Toxicity Category I via the dermal route and Toxicity Category I for skin irritation potential. It is not a skin sensitizer. For this registration, post

- application was not assessed, whereas this action is for a pre

- emergent use. The existing label (Gramozone SL 2.0) lists a 24 hr. REI for other application scenarios.Pag e 28 of 54

10. REFERENCES

Paraquat Dichloride. Request to Expand the Use of Paraquat Dichloride on Potato to Tuber and Corm Vegetables Subgroup 1C

, T. Morton, D 419828

, 9 /2 5 /201 4

.

Paraquat Dichloride : Acute and Chronic Aggregate Dietary Exposure and Risk Assessments for the Registration Request to Expand the Use of Paraquat Dichloride on Potato to Tuber and Corm Vegetables Subgroup 1C

, T.
Morton, D 419827

, 9/25/2014

.

Paraquat

. Occupational and Residential Exposure Assessment for a Proposed Use on Crop subgroup 1C (tuberous and corm vegetables). J.S. Miller, D 419826

, 9/25/2014

.

Review of Jar Test Results for Drinking Water Assessment Purpose

– J

. Lin

, D396402

, 1 / 1 0 /1 2Pag e 29 of 54

APPENDICES

A TOXICOLOGY DATA SUMMARY

A .1 Guideline Data Requirements

Guideline

No. Study Type Technical MRID

No. Required Submitted

870.3100

870.3150

870.3200

870.3250

870.3465 Subchronic (Oral) Toxicity

- Rodent

................................ .............

Subchronic (Oral) Toxicity

- Non

- Rodent

................................ ..... 21/28

- Day Dermal Toxicity

................................ ...........................

90

- Day Dermal Toxicity

90

- Day (21

- day) Inhalation Toxicity

................................ ............ N

Y

N

N

Y N

Y

Y

N

Y 00072416

00156313

00113718

870.3700a

870.3700b

870.3800 Prenatal Developmental Toxicity

- Rodent

................................ ....

Prenatal Developmental Toxicity

- Non

- Rodent

............................ Reproduction and Fertility Effects

................................ ................. Y

Y

Y Y

N

Y 00113714

43964701

00096338

43949902

00126783

00149748

00149749

870.4100a

870.4100b

870.4200a

870.4200b

870.4300 Chronic (Oral) Toxicity

- Rodent

................................ ...................

Chronic (Oral) Toxicity

- Non

- Rodent (Dog)

................................ Carcinogenicity

- R at..................

................................ .............. Carcinogenicity

– Mouse

...... ................................ .......................

Combined Chronic Toxicity /Carcinogenicity

- Rat Y *

Y

Y *

Y

Y N

Y

N

Y

Y 00132472

00087924

40202403

40218001

00138637

870.6100a

870.6100b

870.6200a

870.6200b

870.6300

870.7800 Neurotoxicity

- Acute Delayed Neurotox.

- Hen

............................

Neurotoxicity

- Subchronic

- Hen

................................ ................. Neurotoxicity

- Acute

- Rat

................................ ............................ Neurotoxicity

- Subchronic

- Rat

................................ .................... Developmental Neurotoxicity.................. Immunotoxicity.............................

................................ ........ N

N

Y

Y

N

Y N

N

Y

Y

N

Y 47794201

47794202

48667301

* Satisfied by the Combined Chronic Toxicity /Carcinogenicity

- Rat StudyPag e 30 of 54

A .2 Toxicity Profiles

Table A2 .a. Acute Toxicity Profile

– Paraquat Dichloride

Guideline No. Study Type [species] MRID(s) Results a Toxicity Category

870.1100 Acute oral [rat] 00054573

43685001 LD 50 = 189 (M) or 125 (F)

mg/kg II

870.1200 Acute dermal [rabbit] 00054574 LD 50 = 174 mg/kg (M) I

870.1300 Acute inhalation [rat] b 00046105 LC 50 = 1 μ g/L (M/F) I

870.2400 Acute eye irritation [rabbit] 00054575 Severe irritation I

870.2500 Acute dermal irritation [rabbit] 00054576 Slight to severe irritation;

PIS = 2.1 III

870.2600 Skin sensitization [guinea pig] 00155289 Negative

--

a The test material used in the acute inhalation study was crystalline paraquat dichloride. Purity was not specified, but the purity of crystalline paraquat dichloride used in other studies was 99.9%. The test material used in the other studies was paraquat dichloride in the form of ORTHO Paraquat Concentrate 3 (end use product containing 34.4% paraquat cation). Results are expressed in terms of paraquat dichloride rather than paraquat cation.

b The acute dermal (43685002), eye (43685003) and dermal (43685004) irritation and sensitization (43685005) studies are not displayed above since these s tudies resulted in lower toxicity and thus reduced toxicity category, likely due to a less percent of active ingredient used in the studies ( D217134).Pag e 31 of 54 Table A2 .b. Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/

Classification/Doses Results

870.3150

90

- Day oral toxicity

Beagle dog 00072416 (1981) Acceptable/guideline 0, 7, 20, 60, or 120 ppm (estimated to be 0, 0.2, 0.5, 1.5, and 3 mg/kg/day) NOAEL = 0.5 mg/kg/day

LOAEL = 1.5 mg/kg/day, based on increased lung weight and incidence of alveolitis in both sexes

870.3200

21

- Day dermal toxicity

New Zealand White

rabbit 00 156313 (1986) Acceptable/guideline 0, 0.50, 1.15, 2.60, or 6.00 mg/kg/day Dermal NOAEL = 1.15 mg/kg/day.

Dermal LOAEL = 2.60 mg/kg/day, based on small scabs at the treatment site in both sexes and epidermal erosis/ulceration, surface exudation, acanthosis, and/or

inflammation in males

Systemic NOAEL = 6 mg/kg/day Systemic LOAEL = not obse rved

870.3465

21

- Day inhalation toxicity Sprague

- Dawley rat 00113718 (1979) Acceptable/guideline 0, 0.012, 0.112, 0.487, and

1.280 μg /L NOAEL = 0.012 μ g/L.

LOAEL = 0.112 μg /L, based on squamous keratinizing metaplasia and hyperplasia of the epithelium of the larynx.

870.3700a Prenatal developmental

Wistar rat 00113714 (1978) (initial study) Acceptable/guideline 0, 1, 5, or 10 mg/kg/day Maternal NOAEL = 1 mg/kg/day.

Maternal LOAEL = 5 mg/kg/day, based on mortality, clinical signs of toxicity (piloerection, hunched posture, respiratory distress), microscopic lesions in the lungs and kidney, and decreased body weight gain (BWG).

Developmental NOAEL = 1 mg/kg/day.

Deve lopmental LOAEL = 5 mg/kg/day, based on slightly decreased fetal body weights and on delayed

ossification.

870.3700a Prenatal developmental

Wistar rat 43964701 (1992) (subsequent study) Acceptable/guideline 0, 1, 3, or 8 mg/kg/day Maternal NOAEL = 8 mg/kg/day ( HDT ).

Maternal LOAEL = not observed.

Developmental NOAEL = 8 mg/kg/day ( HDT ). Developmental LOAEL = not observed.

870.3700a Prenatal developmental SPR Alderley Park mice 00096338 (1978) (initial study) Acceptable/guideline 0, 1, 5, or 10 mg/kg/day Maternal NOAEL = 1 mg/kg/day.

Maternal LOAEL = 5 mg/kg/day based on decreased body weight gains.

Developmental NOAEL = 10 mg/kg/day. Developmental LOAEL = not observed.

870.3700a Prenatal developmental

Crl:CD

- 1 (ICR) BR mice 43949902 (1992) (subsequent study) Acceptable/guideline 0, 7.5, 15, or 25 mg/kg/day Maternal NOAEL =15 mg/kg/day.

Maternal LOAEL = 25 mg/kg/day based on mortality, clinical signs of toxicity (piloerection, labored respiration, hunched posture, hypothermia, hypoact ivity, and/or pale extremities and eyes),Pag e 32 of 54 Table A2 .b. Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/

Classification/Doses Results

decreased body weights and body weight gains, increased lung weights, and gross lesions in the lung.

Developmental NOAEL = 15 mg/kg/day. Developmental LOAEL = 25 mg/kg/day based on retardation of the skeleton and decreased fetal body weights.

870.3700a Prenatal developmental

–

non

- rodent Waived per HASPOC memo TXR 0056294

870.3800 Reproduction and fertility effects (3

- generation)

Wistar rat 00126783, 00149748, and 00149749 (1982) Acceptable/guideline 0, 25, 75, or 150 ppm (approximately equivalent to 0, 1.25, 3.75, and 7.5 mg/kg/day) NOAEL = 1.25 mg/kg/day

LOAEL for parental toxicity = 3.75 mg/kg/day, based on increased incidences of alveolar histiocytes.

Offspring NOAEL = 7.5 mg/kg/day. Offspring LOAEL = not observed.

Reproductive NOAEL = 7.5 mg/kg/day. Reproductive LOAEL = not observed.

870.4100b

Chron ic toxicity

Beagle dog 00132472 (1983) Acceptable/guideline 0/0, 0.45/0.48, 0.93/1.00, or 1.51/1.58 mg/kg/day in

males/females NOAEL = 0.45/0.48 mg/kg/day in males/females

LOAEL = 0.93/1.00 mg/kg/day in males/females, based on increased severity of chronic pneumonitis and gross lung lesions in both sexes, and focal pulmonary granulomas in males

870.4200b Carcinogenicity

mouse 00087924 (1981) Acceptable/guideline 0, 0 (two controls), 12.5, 37.5, or 100/125 ppm (estimated to be 0, 0, 1.9, 5.6, and 15.0/18.8 mg/kg/day) NOAEL = 1.9 mg/kg/day.

LOAEL = 5.6 mg/kg/day, based on decreased body weights and food consumption in females, and

increased incidences of renal tubular necro sis, tubular dilatation, and interstitial nephritis in males

No evidence of carcinogenicity

870.4200b Carcinogenicity

JCL:ICR mice 40202403 (1982) Acceptable/guideline 0, 2, 10, 30, or 100 ppm (estimated to be 0, 0.3, 1.5, 4.5, and 15 mg/kg/day) NOAEL = 4.5 mg/kg/day.

LOAEL = 15 mg/kg/day, based on mortality in

females

No evidence of carcinogenicity

870.4300 Chronic/Carcinogenicity

Wistar rat 40218001 (1982) Acceptable/guideline 0, 6, 30, 100, or 300 ppm (equivalent to 0/0, 0.25/0.30,

1.26/1 .50, 4.15/5.12, or 12.25/15.29 mg/kg/day in males/females) NOAEL = 4.15/5.12 mg/kg/day (M/F)

LOAEL = 12.25/15.29 mg/kg/day (M/F), based on mortality

No evidence of carcinogenicityPag e 33 of 54 Table A2 .b. Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/

Classification/Doses Results

870.4300 Chronic/Carcinogenicity

Fischer 344 rat 00138637, 00153223, 40202401, 40202402, and 41317401 (1983) Acceptable/guideline 0, 0 (two controls), 25, 75, or 150 ppm (estimated to be 0,
0, 1.25, 3.75, or 7.5 mg/kg/day) NOAEL = 1.25 mg/kg/day.

LOAEL =3.75 mg/kg/day, based on ocular opacity in females corroborated by le nticular changes observed microscopically

No evidence of carcinogenicity

Gene Mutation

870.5100 Bacterial Gene

Mutation 00100440 (1977) Unacceptable/guideline 1.0, 3.3, 10, 33, 100, 333, or

1000 μg /plate There was no evidence of induced mutant colonies over background.

Gene Mutation

870.5100 Bacterial Gene

Mutation 00100441 (1977) Acceptable/guideline 0.16, 0.8, 4, 20, 100, 500, 2500, or 5000 μg /plate There was no evidence of induced mutant colonies over background.

Cytogenetics

870.5375 In Vitro

Chromosome Aberration 00152692 (1985) Acceptable/guideline

0.75 to 3500 μg /mL There was slight evidence of chromosome aberrations induced over background in the presence and absence

of S9

- activation.

Cytogenetics

870.5385 In Vivo

Chromosome Aberration 40202405 (1987) Acceptable/guideline 15, 75, or 150 mg/kg (33% paraquat ion) There was no evidence of chromosome aberration induced over background.

Other Effects

870.5550 Unscheduled DNA Synthesis 00152693 (1985) Acceptable/gu ideline

10

- 9 , 10

- 8 , 10

- 7 , 10

- 6 , 10

- 5 , 10

-

4 , 10

- 3 , or 10

- 2 M There was no evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures [nuclear silver grain counts] was induced.

Other Effects

870.5550 Unscheduled DNA Synthesis 40202404 (1987) Acceptable/guideline 45, 75, or 120 mg/kg (33% paraquat ion) There was no evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures [nuclear silver grain counts] was induced.

Other Effects

870.5450 Domina nt Lethal Assay 00100442 (year not reported) Acceptable/guideline 0.04, 0.4, or 4 mg/kg/day (23.8% paraquat ion) There was no time

- related positive response of increased pre

- or post

- implantation loss compared to

controls.

Other Effects

870.5915 In Vivo Sister Chromatid Exchange 00152695 (1985) Acceptable/guideline 1.2, 2.5, 12.4, 24.7, 124, 247,
1240, or 2470 μg /mL There was a concentration

- related positive response of SCE induced over background in the presence of S9

- activation. A positive respo nse of SCE induced over background was also observed in the absence of S9

- activation; however, there was no clear dose

- response.

870.6200a Acute Neurotoxicity

- rat 47794201 (2006 ) Acceptable/guideline 0, 25, 75, 250 mg/kg

paraquat NOAEL (neurotoxicity)= 250 mg/kg (84 mg/kg paraquat ion)Pag e 34 of 54 Table A2 .b. Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/

Classification/Doses Results

(0, 8.4, 25.1, 84 mg/kg paraquat ion) (gavage in deionized water)

870.6200b

Subchronic Neurotoxicity

- rat 47794202 (2006 ) Acceptable/guideline 0, 15, 50, 150 ppm (0/0, 1.0/1.1, 3.4/3.9, 10,2/11.9 mg/kg/ bw/day (M/F) (mixed in diet) NOAEL (neurotoxicity)= 150 ppm (10.2/11.9 mg/kg paraquat ion in M/F)

870.7800 Immunotoxicity [feeding ]

- in female

B6C3F1 mice ; 48667301 (2011) Acceptable/guideline 0, 25, 75, or 100 ppm (0, 6.9, 19.9, 27.3 mg/kg bw/day) NOAEL for immunotoxicity = 100 ppm (27.3 mg paraquat dichloride/kg body weight/day). LOAEL for immunotoxicity for both AFC and

NKC assays >100 ppm

.

Systemic NOAEL = 100 ppm (27.3 mg paraquat dichloride/kg body w eight/day), the highest dose

tested. Systemic LOAEL for both AFC and NKC assays is

not established

.
Special studies Rhesus monkey and

humans 00126096

- 00126099 (1982) Acceptable/non

- guideline

607 μg intramuscular injection in monkeys or approximately 9 μg paraquat/cm 2 to the skin of humans (70.0 cm 2 ) Monkeys eliminated 43.5

- 51.5% of the administered radioactivity in the urine within 24 hours after intramuscular injection and 52.3

- 72.3% within 7 days

post

- dose. Following dermal application to humans, total urinary excretion of the applied doses was 0.052

- 0.702% (corrected for incomplete urinary excretion with a rhesus monkey parenteral excretion factor of 58.6%). This result suggests that the compou nd is poorly absorbed through the skin in humans. Peak excretion occurred during the first 24 hours post

- dose.

Dermal Absorption

Non

- guideline 00153439 (1984) In a dermal absorption study with healthy adult male volunteers, 0.3% of the applied 14 C paraquat dichloride was absorbed through the intact skin (forearms, and back of the hands and lower legs) during the 24

- hour exposure period.

A.3 Toxicological Endpoints

A .3.1 Acute Reference Dose (aRfD)

- General Population (Including Infants and Children) and Females Age 13

- 49

Study Selected: Reproduction and fertility effects in rats

MRID Nos.: 00126783, 00149748, and 00149749

Executive Summary: See Appendix A .4Pag e 35 of 54

Dose and Endpoint for Risk Assessment: NOAEL = 1.25 mg/kg/day, based on i ncreased incidences of alveolar histiocytes in both sexes observed at the LOAEL of 3.75 mg/kg/day.

Uncertainty Factor (UF): 100x (10x for interspecies extrapolation and 10x for intraspecies variation)

.

Comments about Study/Endpoint: Although there was no adequate study in which a toxic endpoint could be attributed to a single acute effect, the HIARC (Memo, 4/19/2000) determined

that the 3

- generation reproduction study could be used for the acute RfD because the delayed

toxic effects observed in this study are consistent with acute effects for paraquat poisoning in humans. This decision was confirmed by the current risk assessment team. This study should be used for all population subgroups (i.e, general population including infants and children and females age 13

- 49) because the dose (NOAEL = 1.25 mg/kg/day) is protective of in utero effects and is consistent with the maternal respiratory tract effects (edema in the alveoli and polymorphonuclear infiltration) seen in the developmental rat study at a comparable LOAEL (5.0 mg/kg/day).

aRfD ( General Population

, in cluding infants and children ) = 1.25 mg/kg (NOAEL)

100 ( UF ) = 0.0125 mg/kg

A .3. 2 Chronic Reference Dose ( c RfD)

- General Population (Including Infants and Children) and Females Age 13

- 49

Study Selected: Chronic Toxicity in Dogs

MRID No.: 00132472

Executive Summary: See Appendix A .4

Dose and Endpoint for Establishing a cRfD: NOAEL = 0.45 mg/kg/day, based on increased severity of chronic pneumonitis and gross lung lesions in both sexes, and focal pulmonary granulomas in males observed at the LOAEL of 0.93 mg/kg/day.

Uncertainty Factor(s): 100x (10x for interspecies extrapol ation and 10x for intraspecies variations).

Comments about Study/Endpoint/Uncertainty Factor: This endpoint is based on the primary effect of concern (lung toxicity) and is the lowest NOAEL in the database for chronic effects via

the oral route.

cRf D = 0.45 mg/kg/day (NOAEL)

100 ( UF ) = 0.0045 mg/kg/day

A

. 3

. 4 Incidental Oral Exposure ( S hort

- and I ntermediate

- Term)

As there are no current or proposed residential uses for paraquat, the incidental oral exposurePag e 36 of 54

scenario does not need to be included in this risk assessment.

A

. 3

. 5 Dermal Absorption

Dermal Absorption Factor: 0.3%

Dermal absorption was examined in a series of special studies (MRIDs 00126096

- 00126099). Absorption in humans was estimated to be 0.052

- 0.702% (corrected for incomplete ur inary excretion with a rhesus monkey parenteral excretion factor of 58.6%). These studies were non

guideline and have limited use in risk assessment. However, they provide supplemental

information and

, considering the weight of the evidence, it was concl uded that paraquat is poorly absorbed through the skin. Therefore, a 0.3% dermal absorption factor (HIARC report April 19, 2000), from a study in adult human volunteers, was selected for risk assessment. In this study, the test material was applied to th e forearms a s well as the backs of the hands and legs of the

volunteers for 24 hours.

A

. 3

. 6 Dermal Exposure ( Short

- , Intermediate

- , and Long

- Term )

Short

- and Intermediate

- Term

Study Selected: Multi

- generation Study in Rats

MRID Nos.: 00126783, 00149748, and 00149749

Executive Summary: See Appendix A. 4

Dose and Endpoint for Risk Assessment: NOAEL = 1.25 mg/kg/day, based on increased incidences of alveolar histiocytes in both sexes observed at the LOAEL of 3.75 mg/kg/day.

Comments about Study/Endpoint: The 21

- day dermal toxicity study provided a more sensitive endpoint than did the selected study. However, only localized dermal toxicity was observed in

the 21

- day dermal to xicity study

, whereas the endpoint should be selected based on systemic toxicity. Consequently, the selected reproduction toxicity study in rats provides the most appropriate endpoint for short and intermediate exposure.

The adverse effects noted in th is study were similar to those noted in the acute and short

- term
studies.

As an oral NOAEL was used for this endpoint, a dermal absorption factor of 0.3% (from the adult human study discussed above) should be used in risk assessment.

Dermal Exposure (Long Term)

Study Selected: Chronic Toxicity in Dogs

MRID No.: 00132472Page 37 of 54

Executive Summary: See Appendix A. 4

Dose and Endpoint for Risk Assessment: NOAEL = 0.45 mg/kg/day, based on increased severity of chronic pneumonitis and gross lung lesions in both sexes, and focal pulmonary granulomas in males observed at the LOAEL of 0.93 mg/kg/day.

Comments about Study/Endpoint: The selected chronic toxici ty study in dogs provides the most sensitive endpoint for long

- term exposure. As an oral NOAEL was used for this endpoint, a dermal absorption factor of 0.3% should be used in risk assessment (HIARC report, April 19, 2000).

A .3. 7 Inhalation Exposure ( Short and Intermediate

- Term )

Study Selected: 21

- Day inhalation toxicity study in rats

MRID No.: 00113718

Executive Summary: See Appendix A. 4

Dose and Endpoint for Risk Assessment: The NOAEL = 0.01 μ g/L, based on squamous keratinizing metaplasia and hyperplasia of the epithelium of the larynx noted at the LOAEL of

0.10 μ g/L.

Comments about Study/Endpoint: The lungs are a target organ of paraquat, and paraquat was most toxic when inhaled. The selected study provides the lowest toxic concentration f or this time interval and exposure route. This endpoint is based on the assumption that the particle size is respirable.Page 38 of 54

A.4 EXECUTIVE SUMMARIES

90

- Day Oral Toxicity

– Dog

In a subchronic toxicity study (MRID 00072416) , technical grade paraquat dichloride (32.2% w/w paraquat cation, Mond Reference No.: Y00061/009/004) was administered in the diet to 3 beagle dogs/sex/dose at nominal concentrations of 0, 7, 20, 60, or 120 ppm paraquat cation for up to 13 weeks. Actual intakes are estimated to be 0, 0.2, 0.5, 1.5, and 3 mg/kg/day based on Subdivision F conversion factor of 1 ppm = 0.025 mg/kg/day.

No treatment

- related adverse effects were observed on ophthalmoscopic examination, hematology, clinical chemistry, or urinalysis parameters findings, or during auscultation.

At 60 ppm, absolute and relative to body lung weights were increased by 39

- 56% i n 1 dog/sex. Alveolitis, characterized by a mixture of exudative and proliferative reactions resulting in alveolar collapse, distortion, and interstitial hypercellularity, was observed in 5/6 dogs (vs 0 controls).

The maximum tolerated dose was exceeded at 120 ppm. Two dogs/sex were sacrificed in

extremis during the first month , suffering from marked dyspnea, harsh rales, slow and/or irregular heartbeat, and weight loss. These two dogs lost 0.90

- 1.20 kg. Only 1 dog/sex

survived until terminal sacrifice . Decreased food consumption was noted in the female survivor. Absolute and relative to body lung weights were increased, and alveolitis was observed in all 6 dogs.

The LOAEL is 60 ppm (approximately equivalent to 1.5 mg/kg/day) based on increased lung weight and incidence of alveolitis in both sexes. The NOAEL is 20 ppm (approximately equivalent to 0.5 mg/kg/day).

This study is classified as acceptable/guideline and satisfies the guideline requirement (OPPTS 870.4100b; OECD 452) for a subchronic oral toxicity study in dogs.

870.3200 21

- Day Dermal Toxicity

– Rabbits

In a 21

- day dermal toxicity study (MRID # not provided [ Accession # 260635 ]), paraquat dichloride (43.5% w/w paraquat cation; Lot/Batch # SX

- 1465) in distilled water was applied directly to the hair

- clipped intact skin of 6 New Zealand white rabbits/sex/dose at dose levels of 0, 0.50, 1.15, 2.60, or 6.00 mg/kg/day paraquat catio n for 6 hours/day, 7 days/week during a 21

- day period.

No treatment

- related effects were observed on clinical signs, body weight, body weight gain, food consumption, on hematology or clinical chemistry parameters, or organ weights. All animals survived until scheduled sacrifice. No evidence of systemic toxicity was noted.Page 39 of 54

At 2.60 mg/kg/day, small scabs were noted at the treatment site in 2 males (Days 18 and 21) and 1 female (Days 15, 18, and 21). Microscopically evidence of dermal irritation

was foun d in 3 males and included: epidermal erosis/ulceration, surface exudation, acanthosis, and/or inflammation.

At 6.00 mg/kg/day, very slight to well

- defined erythema was noted in 4

- 6 rabbits/sex at Days 11, 15, 18, and 21. Small scabs were found at the tre ated site in 1

- 2 rabbits/sex on Day 11 and 12/12 rabbits at Days 15, 18, and 21. Large scabs were noted in 2

- 3 rabbits/sex. Grossly, crusty scabs, redness, thickened appearance, and/or prominent subcutaneous vessels were noted. Microscopically, the same lesions were observed as in the 7.8 mg/kg/day group.

The LOAEL is 2.60 mg/kg/day, based on small scabs at the treatment site in both sexes and epidermal erosis/ulceration, surface exudation, acanthosis, and/or inflammation in

males. The NOAEL is 1.15 mg/kg/day.

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 870.3200; OECD 410) for a 21

- day dermal toxicity study in rats.

870.3465 21

- Day Inhalation

– Rat

In a subchronic inhalation toxicity study (MRI D 00113718) , Sprague

- Dawley rats were exposed by whole body inhalation to paraquat dichloride (approximately 40% paraquat ion) administered as a respirable (particle size s < 2 μ m) aerosol at nominal concentrations of 0, 0.01, 0.1, 0.5, or 1.0 μ g/L paraquat ion (equivalent to analytical concentrations of 0, 0.012, 0.112, 0.487, and 1.280 μ g/L, respectively) for 6 hours/day, 5 days/week for 3 weeks. The numbers of rats of each sex assigned to these groups were as follows: 32 (control group); 16 (0.5 μ g/L); a nd 36 (remaining groups). Parameters examined included clinical observations, body weights, food consumption, and water consumption.

At the end of the three

- week treatment period (15 total exposures), 16 rats/sex from the control group and 8 rats/sex/gr oup from the remaining groups were terminated and examined; 8 rats/sex/group were euthanized and examined after a two

- week recovery period. Gross and microscopic examinations were restricted to the respiratory tract (nasal passages, pharynx, tongue, laryn x, trachea, and lungs). The remaining rats (4/sex/dose) in the control, 0.01, and 0.1 μ g/L groups were euthanized after the 5 th exposure, the 15 th
exposure, and 1, 2, and 3 days after the 15 th exposure for paraquat estimations

.

There were no treatment

- related effects on body weights, food consumption, water consumption, or gross pathology at any concentration.

The 1.0 μ g/L group was not exposed after Day 1. Of the rats in this group, 28/36 males (78%) and 29/36 females (80%) died from respira tory failure in the subsequent 14 days.

All rats in the 0.1 μ g/L group exhibited nasal discharge and squamous keratinizing metaplasia, and/or hyperplasia of the epithelium of the larynx. The changes in thePage 40 of 54

epithelium were still observed in 11/16 (69%) of the rats euthanized at the end of the recovery period.

Additionally in the 0.5 μ g/L group, the following findings were observed after 3 weeks: (i) extensive ulceration, necrosis, inflammation and squamous keratinizing metaplasia, and marked/moderate hype rplasia of adjacent epithelia in larynx of all rats; and (ii) aggregations of foamy macrophages in the bronchioles or alveoli, hypertrophy of the epithelium and thickened alveolar walls in the lungs of most or all rats. After the 2

- week recovery period, n o ulceration or necrosis was observed in the larynx, but changes in the lungs were still seen. In addition, disruption of bronchiolar epithelium, adjacent to the macrophage aggregation, was noted.

At 0.01 μ g/L, there were no treatment

- related effects on any parameter.

The LOAEL is 0.10 μ g/L based on squamous keratinizing metaplasia and hyperplasia of the epithelium of the larynx. The NOAEL is 0.01 μ g/L.

At the request of the Agency, this study was conducted for a duration of three weeks,

instead of the 90 days required by Guideline OPPTS 870.3465. Aside from the different study duration, this study was conducted in accordance with Guideline OPPTS 870.3465.

This 21

- day inhalation toxicity study is classified as acceptable/guideline and satisfies the

gu ideline requirement (OPPTS 870.3465; OECD 413) for a subchronic inhalation study

in the rat.

Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study

– Rat

In a developmental toxicity study (MRID 00113714) , paraquat dichloride (1 00% technical grade; Batch # ADYM76/C; 38% w/v paraquat ion) in 0.5% aqueous Tween 80 was administered daily via oral gavage to 29

- 30 presumed pregnant Alderly Park Wistar

derived (Alpk:SPF SD) rats/group at a dose volume of 10 mL/kg at dose levels of 0, 1 , 5, or 10 mg/kg/day of paraquat ion from gestation day (GD) 6 through 15. All surviving dams were killed on GD 21. The lungs and kidneys from at least 11 surviving dams/group were examined microscopically. The fetuses were removed by cesarean

section a nd examined.

One 5 mg/kg/day dam had excessive blood loss from the vagina and was euthanized on

GD 18. At ≥ 5 mg/kg/day, clinical signs of toxicity included piloerection, weight loss, hunched appearance, and respiratory distress. Earliest onset of these signs occurred on GD 8, with weight loss, thin appearance, and slightly hunched posture observed in a single animal (#71); and slight piloerection was noted in another dam (#83) on the following day. Clinical signs of toxicity became more prevalent, affec ting more animals more frequently, from GD 13

- 21. Body weight gains were decreased by 37

- 74% during the treatment (GD 6

- 16) interval (calculated by the reviewers; statistics not performed)Page 41 of 54

and by 24

- 29% for the overall (GD 0

- 21) study (p ≤ 0.001).

Additionally at 10 mg/kg/day, one female (# 92) delivered prematurely on GD 21. An additional 14 dams died or were sacrificed moribund prior to scheduled termination. Morbidity considered to be due to the test substance was observed in 6 of these dams. Gross necropsy indicated that the lungs were red and patchy, and microscopic examination revealed large amount of edema fluid and polymorph infiltration in the alveoli, while the kidneys showed widespread degenerative change in the proximal

tubules. It wa s stated that the deaths of the remaining dams in this dose group were likely due to gavage error.

The maternal LOAEL is 5 mg/kg/day based on mortality, clinical signs of toxicity, and decreased body weight gains. The maternal NOAEL is 1 mg/kg/day.

The re was no effect on the proportion of dams having one or more resorptions, and there

were no treatment

- related effects on sex ratio or embryonic or fetal survival. There were no increases in fetal external visceral, or skeletal malformations or variations at any dose tested, indicating that paraquat dichloride is not teratogenic in rats at the dose levels

tested.

At ≥ 5 mg/kg/day, fetal body weights were reduced by 3

- 6%. Skeletal ossification was slightly retarded in these groups, as indicated by decrease d ossification of the caudal vertebrae and decreased degree of ossification in the digits in the fore

- and hind

- limbs. The percent of fetuses with 7 or 8 caudal vertebrae ossified was decreased (p ≤ 0.05) at this dose (8% treated vs 26% controls). The perc ent of fetuses with “good” (Grade 2) ossification in the digits in the fore

- limbs was dose

- dependently decreased at 5 (29%) and 10 (23%) mg/kg/day compared to controls (42%). The percent of fetuses with Grade 2 or 3 ossification in the digits in the hind

- limbs was dose

- dependently decreased at ≥ 5 mg/kg/day (20% each treated) compared to controls (42%). Likewise, the percent of fetuses with “poor” (Grade 5) ossification in the digits of the hind limbs was increased at

≥ 5 mg/kg/day (23

- 32%) compared to cont rols (13%). These decreases in growth and development are probably associated with the maternal toxicity observed at this dose.

The developmental LOAEL is 5 mg/kg/day based on slightly decreased fetal body weights and on delayed ossification. The develo pmental NOAEL is 1 mg/kg/day. This study is classified acceptable/guideline and satisfies the guideline requirements (OPPTS 870.3700a) for a developmental study in the rat.

In a developmental toxicity study (MRID 43964701) , paraquat dichloride (38.2% w/v paraquat ion) in deionized water was administered daily via oral gavage to 24 presumed pregnant Alderley Park, Wistar

- derived (Alpk:APfSD) rats/group at a dose volume of 10 mL/kg at dose levels of 0, 1, 3, or 8 mg/kg/day from gestation day (GD) 7 through 1 6. All surviving dams were killed on GD 22. The fetuses were removed by cesarean section

and examined.

There were no effects of treatment on mortality, clinical signs, body weights, bodyPage 42 of 54

weight gains, food consumption, or gross pathology.

The maternal LOAEL was not observed. The maternal NOAEL is 8 mg/kg/day (highest dose tested).

There were no premature deliveries or complete litter resorptions and no effects of treatment on the numbers of live fetuses, early resorptions, late resorptions, or post

im plantation loss, indicating no effect on embryonic or fetal survival. In the fetuses,

there were no treatment

- related external, visceral, or skeletal malformations or variations, indicating that paraquat dichloride is not teratogenic in rats at the dose l evels tested.

The developmental LOAEL was not observed. The developmental NOAEL is 8 mg/kg/day (highest dose tested).

A LOAEL was not observed in this study, but the dose range tested did not include the limit dose (1000 mg/kg/day). However, maternal rats exhibited mortality, clinical signs of toxicity, and microscopic lesions in the lungs and kidney in a previous study (MRID 00113714) conducted by the performing laboratory in 1978 using the same strain of rat.

Because death was observed at 5 and 10 m g/kg/day in the previous study, the dose levels for the current study were lowered slightly to a maximum dose level of 8 mg/kg/day. Thus, the current study is acceptable for regulatory purposes. For the purpose of risk characterization, the NOAEL from th e older study should continue to be used until additional data have been received to support any changes.

This study is classified acceptable/guideline and satisfies the guideline requirements (OPPTS 870.3700a) for a developmental study in the rat.

870.3700b Prenatal Developmental Toxicity Study

– Mouse

In a developmental toxicity study (MRID 00096338) , paraquat dichloride (100% technical grade; 38% w/v paraquat ion) in 0.5% aqueous Tween 80 was administered daily via oral gavage to 30 mated female SPF Alderley Park mice/group at a dose volume of 10 mL/kg at dose levels of 0, 1, 5, or 10 mg/kg/day of paraquat ion from gestation day (GD) 6 through 15. Because several mice in each group either died, littered early, or

were not pregnant

, an insufficien t number of litters were available for teratology assessment. Therefore, 4

- 5 weeks after the first matings, an additional 42 mice were mated; and 6, 6, 20, and 10 mice were allocated to the 0, 1, 5, or 10 mg/kg/day groups, respectively. All surviving dam s were killed on GD 18. The lungs and kidneys from at least 8 surviving dams/group were examined microscopically. The fetuses were removed by cesarean section and examined.

There were no treatment

- related effects on mortality, clinical signs, food consu mption, water consumption, gross pathology, or histopathology. Body weight gains for the treatment period (GD 6

- 15) were decreased by 22% at 5 mg/kg/day and by 13% at 10 mg/kg/day, resulting in decreased body weight gains for the overall (GD 0

- 18) study o f 14% (p ≤ 0.05) at 5 mg/kg/day and 11% (not significant) at 10 mg/kg/day.Page 43 of 54

The maternal LOAEL is 5 mg/kg/day based on decreased body weight gains. The maternal NOAEL is 1 mg/kg/day.

The numbers of viable fetuses and resorptions and the sex ratio, fetal we ights, and litter weights in the treated groups were comparable to controls. There were no treatment

related fetal external, visceral, or skeletal malformations, variations, or retardations.

The developmental LOAEL was not observed. The developmental N OAEL is 10 mg/kg/day.

This study is classified acceptable/guideline and satisfies the guideline requirements (OPPTS 870.3700a) for a developmental toxicity study in the mouse.

In a developmental toxicity study (MRID 43949902) , paraquat dichloride (38.2% w/v paraquat ion) in deionized water was administered daily via oral gavage to 26 mated

female Crl:CD

- 1 (ICR) BR mice/group at a dose volume of 10 mL/kg at dose levels of 0, 7.5, 15, or 25 mg paraquat ion/kg/day from gestation day (GD) 6 through 15. All surviving dams were killed on GD 18. The lungs (with trachea) and kidneys were removed, weighed, and fixed in buffered formal saline, but were not examined microscopically. The fetuses were removed by cesarean section and examined.

There were no treatme nt

- related effects on maternal food consumption.

At 25 mg/kg/day, one dam was found dead on GD 16, with no clinical signs of toxicity observed prior to death. Four other dams at this dose were euthanized prior to scheduled termination due to poor condition on GD 15

- 17. Clinical signs of toxicity in these dams included piloerection, labored respiration, hunched posture, hypothermia, hypoactivity, and/or pale extremities and eyes. Additionally at this dose, body weights were decreased by 6

- 9% (p<0. 05) during GD 15

- 18 compared to controls. Body weight gains were decreased (p<0.01) by 22% for the treatment period (GD 6

- 15) and by 29% for the post

treatment period, resulting in decreased (p<0.01) body weight gains for the overall (GD

0

- 18) study of 19 %. When adjusted for gravid uterine weight, body weight gains were still decreased by 18% (not significant). Dark red lung lobes were observed in the dam that was found dead, in all four of the dams sacrificed in moribund condition, and in four

additiona l dams at termination (for a total of 35% treated vs 0% controls). Absolute and relative (to body) lung weights were increased (p<0.01) by 31

- 64% in these animals.

There were no effects of treatment at 7.5 or 15 mg/kg/day.

The maternal LOAEL is 25 mg/kg /day based on mortality, clinical signs of toxicity, decreased body weights and body weight gains, increased lung weights, and gross lesions in the lung. The maternal NOAEL is 15 mg/kg/day.

There were no premature deliveries or complete litter resorption s and no effects of treatment on the numbers of litters, fetuses (live or dead), resorptions (early or late), or onPage 44 of 54

sex ratio or post

- implantation loss. There were no treatment

- related fetal external, visceral, or skeletal malformations.

At 25 mg/kg/day, fetal body weights were decreased (p<0.01) by 9

- 10% compared to controls. Retardation of the skeleton was indicated by increases (p<0.05) in the numbers of: litters with retarded ossification of the occipital bone (42.9% treated vs 8.3% controls); fetus es and litters with ≤ 6 caudal centra (47.0% fetuses in 57.1% treated litters vs 7.0% fetuses in 20.8% control litters); litters with uni

- or bi

- lateral extra 14 th ribs (64.3% treated vs 29.2% controls); and fetuses and litters with non

- ossified astragalus in the hind limb (36.1% fetuses in 57.1% treated litters vs 8.9% fetuses in 20.8% control litters).

There were no effects of treatment at 7.5 or 15 mg/kg/day.

The developmental LOAEL is 25 mg/kg/day based on retardation of the skeleton and

decreased feta l body weights. The developmental NOAEL is 15 mg/kg/day.

This study is classified acceptable/guideline and satisfies the guideline requirements (OPPTS 870.3700a) for a developmental toxicity study in the mouse.

Reproductive Toxicity

870.3800 Reproduction and Fertility Effects

– Rat

In a three

- generation reproduction toxicity study (MRIDs 00126783, 00149748, and 00149749) , technical grade paraquat dichloride (32.7% w/v paraquat cation) was administered continuously in the diet to Wistar

- derive d Alderley Park rats (15 males and 30 females/dose) at dose levels of 0, 25, 75, or 150 ppm (approximately equivalent to 0, 1.25, 3.75, and 7.5 mg paraquat ion/kg/day, assuming that for an older rat, 1 ppm = 0.05 mg/kg/day). Parents were fed test diets fo r 11

- 12 weeks before they were mated to produce the F1, F2, and F3 litters. The F1a pups were weaned on postnatal day (PND) 21, but were not bred. P generation rats were re

- mated 7 days later to produce the F1b litters, which were weaned on PND 28 and ho used until PND 35. From the F1b litters, 15 males and 30 females/dose were fed the test diets and bred for the production of the F2a and F2b litters. This process was repeated to produce the F3a and F3b litters. The study was terminated after the F3b li tters were weaned.

There were no effects of treatment on clinical signs, body weights, body weight gains, food consumption, food utilization, ophthalmology, hematology, clinical chemistry, or urinalysis.

In all generations, alveolar histiocytosis was inc reased in the 75 (10

- 71%) and 150 (50

- 86%) ppm males compared to controls (11

- 30%) and in the 75 (62

- 80%) and 150 (80

- 100%) ppm females compared to controls (28

- 40%).

High mortality was observed in the 150 ppm P, F1, and F2 females (17

- 43%) comparedPage 45 of 54

to co ntrols (0

- 4%). These deaths were considered to be due to severe lung damage caused by paraquat. The incidence of lung lesions (red or purple discoloration, congestion, edema, fibrosis, hyaline membrane formation, inflammatory cell infiltration, and/or hy perplasia) ranged from 27

- 35% in these animals compared to 0 controls.

At termination, the most frequent microscopic findings were hydronephrosis, nephrocalcinosis, lung congestion and/or alveolar hemorrhage, perivascular inflammatory

cell infiltration in the lungs, focal accumulation of lymphocytes in the liver, and hypoplasia, atrophy, and/or necrosis of the testes. However, the incidences of these findings were not dose

- related.

The LOAEL for parental toxicity is 75 ppm (approximately equivalent to 3.75 mg paraquat ion/kg/day), based on increased incidences of alveolar histiocytes in both sexes. The NOAEL is 25 ppm (equivalent to 1.25 mg paraquat ion/kg/day).

There were no effects of treatment on maternal neglect index (% dams with all pups dead by PND 10), lactation index (i.e., survival to PND 21), litter size (viability) from PND 0 through 28, or litter weight gain.

The LOAEL for offspring toxicity was not observed. The NOAEL is 150 ppm (approximately equivalent to 7.5 mg/kg/day).

There were no effects of treatment on fertility, gestation duration, or live birth index.

The LOAEL for reproductive toxicity was not observed. The NOAEL is 150 ppm (approximately equivalent to 7.5 mg/kg/day).

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 870.3800; OECD 416) for a multi

- generation reproduction study in the rat.

Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity

– Rat

In this combined chronic toxicity/carcinogenicity study (MRIDs 00138637, 00153223, 40202402, 40202401, and 41317401) , paraquat dichloride (96.1% a.i.; Batch #: S 358)

was administered in the diet to 70 Fischer 344 rats/sex/dose at nominal concentrations of 0, 0 (two controls), 25, 75, or 150 ppm for up to 117 weeks in males and 124 weeks in females. All doses are for the paraquat cation, and group mean actual intakes for the entire study period were not reported. Actual intakes are estimated by the reviewers to be 0, 0, 1.25, 3.75, and 7.5 mg/kg/day based on Subdivis ion F conversion factor of 1 ppm = 0.050 mg/kg/day. Ten rats/sex/dose were sacrificed at Week 52, and paraquat levels were determined in the tissues and plasma of 5 rats/sex/dose.

No adverse, treatment

- related effects were observed on mortality, food con sumption, water consumption, or on any hematological, clinical chemistry, or urinalysis parameters.Page 46 of 54

At 150 ppm, body weights were decreased (p ≤ 0.05) at Weeks 26, 52, 78, 104, and 113 by

6

- 8% in males and at Weeks 52, 78, 104, 117 , and 122 by 2

- 10% in fe males. Body weight gain (Weeks 0

- 104) were decreased by 11% in males and 9% in females (calculated by reviewers. Food utilization was decreased during Weeks 13

- 26, 27

- 40,

and 41

- 52 (last week calculated) by 8

- 21% in both sexes.

The eyes were a target or gan. During clinical observations, eye opacity was observed in the 75 and 150 ppm females (23

- 58% treated vs 5% controls) and 150 ppm males (37% vs 7%). Opacities were first observed during the first year, but were rare until after Week

101 in males and Week 111 in females. During ophthalmoscopic examinations, increased incidences (% treated vs % controls) of the following findings were observed at 150 ppm: (i) posterior polar opacity/cataract in males (41% vs 7%) and females (64% vs 0%); (ii) posterior capsular opacity/cataract in males (52% vs 0%) and females (26% vs 4%); (iii) radial cataract in both sexes (11

- 17% vs 0%); (iv) cataracts in both sexes (9

- 11% vs 2%); and (v) lens resorption in both sexes (6

- 9% vs 0%). Increased incidences of

lens lesion s were also observed in the 150 ppm group at Weeks 110 and at termination. Only minor increases in eye lesions were noted before Week 103. Microscopically, increased incidences of the following ocular lesions were observed in all treated groups (both sexe s) at termination of the study: peripheral Morganian corpuscles, peripheral lenticular degeneration, mid

- zonal lenticular degeneration, and a pear

- shaped posterior peripheral lenticular change. Clinical observations and ophthalmoscopic examinations

did no t corroborate ocular toxicity at 25 ppm. Additionally, increased incidences of the following ocular lesions were noted in the 150 ppm males: lens capsule fibrosis, lens capsule rupture, peripheral retinal degeneration of the outer nuclear layer, posterior synechia, proteinaceous aqueous humor, and vitreous cellularity.

At 150 ppm, the lungs were also a target organ. At the interim sacrifice, an increase in alveolar pigmented macrophages was observed in the females (40% treated vs 20% controls). Relative to body lung weights were increased by 14

- 16% in both sexes at

stu dy termination. Grossly, increased incidences of occasional or multiple, dark or pale subpleural foci/areas were observed at the terminal sacrifice in males (21/33 treated vs 2/60 controls) and females (22/29 treated vs 10/58 controls). Increased inciden ces (n=55

- 60) were noted of alveolar epithelialization (16% vs 3%) and increased number of macrophages (17% vs 2%) in males and accumulation of alveolar macrophages in females (37% vs 19%).

The following observations were considered equivocal due to a la ck of corroborating evidence of toxicity: an increased incidence (n=55

- 60) of degeneration of sciatic nerve fibers was observed in the 75 and 150 ppm males (53

- 54% treated vs 32% controls); an increased incidence of hydrocephalus was observed in the 75 and 150 ppm females (21

- 34% treated vs 12% controls).

Small amounts of the paraquat cation were detected in one or more treated groups in the lungs, liver, kidneys, skin, and plasma in animals sacrificed after 52 weeks of treatment. At the high dose, conce ntrations ranged from 0.037

- 0.71 μ g/g.Page 47 of 54

The LOAEL is 75 ppm (approximately equivalent to 3.75 mg/kg/day), based on ocular opacity in females corroborated by lenticular changes observed microscopically. The NOAEL is 25 ppm (approximately equivalent to 1.25 mg/kg/day).

At the doses tested, there was a treatment related increase in tumor incidence when compared to controls. The incidences of the following tumors were increased (n=69

- 70; % in treated group[s] vs concurrent controls vs reference range of the animal provider): pulmonary adenomas in the 75 and 150 ppm males (6

- 7% treated vs 1% controls vs 1.4

- 5.6% reference) and in the 75 and 150 ppm females (3

- 11% treated vs 0% controls vs

0.8

- 1.7% reference); pulmonary carcinoma in the 150 ppm males (4% treate d vs 1%

controls vs 0.8

- 2.2% reference) and all treated female groups (1

- 3% treated vs 0% controls vs 0% reference). Additionally in the 150 ppm males at the terminal sacrifice (n=23

- 33), increased incidences were noted of benign pheochromocytoma in the a drenals (27% treated vs 10% controls) and thyroid parafollicular adenoma (33% treated vs 17% controls). Dosing was considered adequate based on eye and lung toxicity, and reduced body weights, body weight gains, and food utilization.

This study is accept able/guideline and satisfies the guideline requirement for a chronic/ carcinogenicity study (OPPTS 870.4300; OECD 453) in rats.

870.4100b Chronic Toxicity

– Dog

In a chronic toxicity study (MRID 00132472) , technical grade paraquat dichloride (32.3% w/w paraquat cation, Mond Reference No.: S358/2) was administered in the diet to 6 beagle dogs/sex/dose at nominal concentrations of 0, 15, 30, or 50 ppm (equivalent to 0/0, 0.45/0.48, 0.93/1.00, and 1.51/1.58 m g/kg/day paraquat cation in males/females) for up to 52 weeks.

No treatment

- related adverse effects were observed on mortality, body weights, body weight gains, or on ophthalmoscopic examination, hematology, clinical chemistry or urinalysis parameters.

Increased incidences of the following clinical signs were observed at 50 ppm in both sexes: hypernea (4/6 vs 1/6, each sex), increased vesicular sound (3

- 4/6 vs 0/6), and reddening of tongues (6/6 vs 4/6, each sex). The frequency of these observations wa s also increased at 50 ppm. These signs were first observed at Week 13 (hypernea and increased vesicular sound) and week 9 (tongue reddening). Food consumption was decreased in one 50 ppm dog/sex. The hypernea was corroborated by further findings of pul monary toxicity. The other findings are considered equivocal.

Lungs were the target organ. Absolute and relative to body lung weight were each increased by 36% in males and 61% in females at 50 ppm. Chronic pneumonitis was observed in 44 of the 48 dogs that were evaluated; therefore, an increased incidence was not observed. However, an increase in severity was observed in the 30 and 50 ppmPage 48 of 54

groups; the incidence (# affected/6, treated vs controls) of slight to marked chronic pneumonitis was 5

- 6 treated males vs 2 controls and 3

- 6 treated females vs 1 control. This lesion correlated to yellow discoloration and consolidation of areas of the lungs observed grossly. Additionally, the incidence and severity of minimal to moderate focal granuloma was increas ed in the 30 and 50 ppm males (5/6 each treated vs 4/6 controls). Focal pleural fibrosis was observed in 3/6 males at 50 ppm vs 2/6 controls and may have

been treatment

- related.

Small amounts of the paraquat cation were detected in the lungs of all treat ed groups (0.13

- 1.04 μ g/g) and in the kidney of the 30 and 50 ppm groups (0.12

- 0.19 μ g/g).

The LOAEL is 30 ppm (equivalent to 0.93/1.00 mg/kg/day in males/females) based on increased severity of chronic pneumonitis and gross lung lesions in both sexes, and focal pulmonary granulomas in males. The NOAEL is 15 ppm (equivalent to 0.45/0.48 mg/kg/day in males/females).

At the doses tested, there was no treatment

- related increase in tumor incidence when compared to controls. Dosing was considered adequate based on an increase in pulmonary toxicity.

This study is classified as acceptable/guideline and satisfies the guideline requirement (OPPTS 870.4100b; OECD 452) for a chronic oral toxicity study in dogs.

Carcinogenicity

870.4200a Carcinogenicity Study

– rat

In this combined chronic toxicity/carcinogenicity study (MRID 40218001) , paraquat dichloride ( ≥ 98% a.i.; Lot #: 540108) was administered in the diet to 50 Wistar rats/sex/dose at nominal concentrations of 0, 6, 30, 100, or 300 ppm (equivalent to 0/0, 0.25/0.30, 1.26/1.50, 4.15/5.12, and 12.25/15.29 mg/kg/day in males/females) for up to

104 weeks. A dditionally 12 rats/sex/dose were treated similarly, and 6 rats/sex/dose were

sacrificed at Weeks 26 and 52.

No adverse, treatment

- related effects were observed on body weight, body weight gains, food consumption, or on any ophthalmoscopic examination, hematological, clinical chemistry, or urinalysis parameters, organ weights, or gross and histological pathology.

Increased mortality was observed in the 300 ppm males ( ↑ 26%) and females ( ↑ 10%). In moribund animals, decreased spontaneous mobility, loss o f coat luster, and piloerection

were noted.

The LOAEL is 300 ppm (equivalent to 12.25/15.29 mg/kg/day), based on mortality. The NOAEL is 100 ppm (approximately equivalent to 4.15/5.12 mg/kg/day).Page 49 of 54

At the doses tested, there was no treatment

- related incre ase in tumor incidence when compared to controls. Dosing was considered adequate based on decreases in survival in

both sexes.

This study is acceptable/guideline and satisfies the guideline requirement for a chronic/ carcinogenicity study (OPPTS 870.4300 ; OECD 453) in rats.

870.4200b Carcinogenicity (feeding)

– Mouse

In a carcinogenicity study ( MRID 00087924 ), 60 Swiss

- derived mice/sex/dose were exposed to paraquat dichloride (96.1% a.i.; Batch #: S 358/1) in the diet at nominal concentrations of 0, 0 (two controls), 12.5, 37.5, or 100/125 ppm for up to 99 weeks. All doses are for paraquat cation, and actual intakes were not reported. Actual intakes were estimated to be 0, 0, 1.9, 5.6, and 15.0/18.8 mg/kg/day based on Subdivision F

conversion factor of 1 ppm = 0.150 mg/kg/day. Animals in the high dose group received 100 ppm for the first 35 weeks and 125 ppm for the remainder of the study because no signs of toxicity were observed at 100 ppm. An additional 10 mice/sex/dose were treated similarly, an d paraquat levels were determined in the tissues and plasma at 52 weeks.

Blood and urine analysis (except for determination of paraquat levels) were not performed and no organ was weighed. No treatment

- related effect was observed on food

utilization.

At 37.5 ppm, the following findings were noted: in females, decreased body weights beginning at Week 68 ( ↓ 5

- 20%) and decreased food consumption at Weeks 6

- 20 ( ↓ 3

- 15%) and 56

- 84 ( ↓ 15

- 22%); in males, increased incidences (% treated vs % controls,

observed at terminal kill) of renal tubular necrosis (38% vs 8%), tubular dilatation (8% vs 0%), and interstitial nephritis (23% vs 15%).

At 100/125 ppm, the findings at 37.5 ppm were more severe, and the following additional findings were observed: increased inciden ces of hypercellularity of alveolar walls, renal tubular necrosis, tubular dilatation, and pelvic dilatation in both sexes; lung congestion and alveolar macrophages in females; and also increased mortality in females.

Small amounts of the paraquat ion were detected at 100/125 ppm in the plasma (0.051

- 0.056 μ g/ml), kidneys (1.17

- 1.61 μ g/g), and lungs (0.43

- 0.52 μ g/g) of both sexes. Paraquat cation levels in other tissues were not reported.

The LOAEL is 37.5 ppm (approx imately equivalent to 5.6 mg/kg/day) based on decreased body weights and food consumption in females, and increased incidences of renal tubular necrosis, tubular dilatation, and interstitial nephritis in males. The NOAEL is 12.5 ppm (approximately equival ent to 1.9 mg/kg/day).

At the doses tested, there was no treatment

- related increase in tumor incidence when compared to controls. Dosing was considered adequate based on decreases in survival,Page 50 of 54

body weights, food consumption, nephrotoxicity, and lung toxi city.

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 870.4200b; OECD 451) for a carcinogenicity study in mice.

In a carcinogenicity study (MRID 40202403) , 80 JCL:ICR mice/sex/dose were exposed

to paraquat dichloride ( ≥ 98% a.i.; Lot #: 540108) in the diet at nominal concentrations of 0, 2, 10, 30, or 100 ppm for up to 104 weeks. All doses are for paraquat cation, and actual intakes were not reported. Actual intakes were estimated to be 0, 0.3, 1.5, 4.5, a nd 15 mg/kg/day based on Subdivision F conversion factor of 1 ppm = 0.150 mg/kg/day. Interim sacrifices of 10 mice/sex/dose were performed at 26 and 52 weeks.

No treatment

- related effect was observed on body weights, body weight gains, food consumption, food efficiency, or on hematology, clinical chemistry, or urinalysis findings, organ weights, or gross or histological pathology.

Mortality was increased by 13% in the 100 ppm females; moribund animals had lower spontaneous mobility, loss of coat luster, and piloerection.

The LOAEL is 100 ppm (approximately equivalent to 15 mg/kg/day) based on mortality in females. The NOAEL is 30 ppm (approximately equivalent to 4.5 mg/kg/day).

At the doses tested, there was no treatment

- related increase in tumor incid ence when compared to controls. Dosing was considered adequate based on decreases in survival in

females.

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 870.4200b; OECD 451) for a carcinogenicity study in mice.

870.5100, 870

- 5300, 870.5375, 870.5900 Mutagenicity

Gene Mutation

870.5100; Bacterial Gene Mutation

MRID 0010440 Unacceptable/Guideline There was no evidence of induced mutant colonies over background up to

1000  g/plate.

870.5100; Bacterial Gene Mutation

MRID 0010441 Acceptable/Guideline There was no evidence of induced mutant colonies over background up to

5000  g/plate.

Cytogenetics

870.5375; In vitro Chromosome

Aberration

MRID 00152692 Acceptable/Guideline There was slight evidence of chromosome aberrations induced over background in the presence and absence of S9 activation.Page 51 of 54

870.5385; In vivo Chromosome

Aberration

MRID 40202405 Acceptable/Guideline There was no evidence of induced chromosome aberration over background in the presence and absence of S9 activation.

Other Genotoxicity

870.5550; Unscheduled DNA Synthesis

MRID 00152693 Acceptable/Guideline There was no evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures, was induced.

870.5550; Unscheduled DNA Synthesis

MRID 40202404 Acceptable/Guideline There was no evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures, was induced.

870.5450; Dominant Lethal Assay

MRID 00100442 Acceptable/Guideline There was no time

- related positive response of increased pre

- or post

implantation loss compared to controls.

870.5915; In Vivo Sister Chromatid Exchange

MRID 00152695 Acceptable/Guideline There was a concentration

- related positive response of SCE induced over background in the presence of S9

- activation. A positive response of SCE induced over background was also observed in the absence of S9

- activation; however, there was no clear dose

- response.

Neurotoxicity

In an acute neurotoxicity study (MRID 47994201 ) , groups of fasted 42 day

- old Alpk:Ap f SD rats 10/sex/dose were given a single oral dose of paraquat technical (33.4% w/w paraquat ion, 46.1% w/w paraquat dichloride, preparation P47) in deionized water orally (by gavage) at 10 mL/kg at doses of 0, 25, 75, or 250 mg/kg paraquat technical/kg body weight. This corresponded to doses of 0, 8.4, 25.1, and 84 mg/kg paraquat ion. Animals were observed for 14 days after dosing. Neurobehavioral assessment (functional observational battery and motor activity testi ng) was performed in 10/sex/group one week prior to dose administration, at approximately 2 hours after dose administration on Day 1, and at one week (Day 8) and two weeks (Day 15). At study termination,

5 /sex/group were euthanized and perfused in situ fo r neuropathological examination. Of the perfused animals, 5/sex/group of control and 250 mg/kg animals were subjected to histopathological evaluation of brain and peripheral nervous system tissues.

No effects of the test chemical were observed in the fu nctional observational battery, or on motor activity and nervous system histopathology.

One 250 mg/kg male dosed with paraquat technical (84 mg/kg paraquat ion) was found dead on Day 5. This male had shown a slightly reduced foot splay reflex on Days 1

- 4 with piloerection and “sides pinched in” on Day 4. One 250 mg/kg female was killed on Day 4, due to adverse clinical signs of irregular breathing (indicative of respiratory distress), flaccidity, “sides pinched in”, and upward spinal curvature from Day s 2

- 4, andPage 52 of 54

piloerection and ocular discharge on Days 3

- 4. These deaths were considered treatment

related. All other animals survived to scheduled sacrifice. The death and respiratory distress observed in the high

- dose animals are consistent with the kno wn pulmonary toxicity of paraquat.

The LOAEL for neurotoxicity was not observed. The NOAEL is 250 mg/kg paraquat technical (84 mg/kg paraquat ion).

This neurotoxicity study is classified as acceptable, guideline and satisfies the guideline requirement for an acute neurotoxicity study in rats (870.6200; OECD 424).

In a subchronic neurotoxicity study (MRID 47994202 ) paraquat technical ( 33.4% (w/w) paraquat ion, 46.1% (w/w) paraquat dichloride, Batch 216, prepara tion reference P47) was administered to Alpk:Ap f SD rats 12/sex/group at dose levels of 0, 15, 50, or 150 ppm (equivalent to 0, 1.0/1.1, 3.4/3.9, 10.2/11.9 mg/kg bw/day of paraquat cation in males/females) for 13 weeks. Cage side observations were recorded daily. Detailed clinical observations, including the finding of “no abnormalities detected” were recorded weekly. Neurobehavioral assessment (functional observational battery and motor activity testing) was performed in 10 animals/sex/group one week pri or to dosing (pre

- test) and in Weeks 1, 4, 8, and 13 of dosing. At study termination, 5/sex/group were euthanized and perfused in situ for neuropathological examination. Of the perfused animals, 5/sex/dose control and 150 ppm animals were subjected to hi stopathological evaluation of brain and peripheral nervous system tissues.

There were no clinical signs associated with the test material, and no effects of the test material were observed in the functional observational battery. There were also no

effec ts of the test material on motor activity. There were also no effects of the test material on brain weights and there were no neuropathological findings.

Dosing was considered adequate, based on a previous stud y

.

The NOAEL for subchronic neurotoxicity was 150 ppm (equivalent to 10.2

- 11.9 mg paraquat cation/kg in males/females). The LOAEL was not observed.

The study is classified as acceptable, guideline and satisfies the guideline requirement

for a subchronic ne urotoxicity study in rats (870.6200b).

Metabolism

870.7485 Metabolism

- Rat

Non

- Guideline Metabolism and Dermal Penetration

In a special study (MRIDs 00126096

- 00126099) , a single dose of 607 μ g [ 14 C

- methyl]Page 53 of 54

paraquat dichloride (99.8% radiochemical purity, Lot No. not reported) in distilled water was injected intramuscularly into each of 4 adult male Rhesus monkeys. 24

- hour urine samples were collected daily for 7 days. In another experiment, a single dose of the same test compound was applied to the skin (70.0 cm 2 ) of 6 community volunteers (ages 30

- 74) at approximately 11.83 μ g paraquat dichloride/cm 2 . Data were collected for bilateral applications at 3 different sites: ventral forearms, back of hands, or lower legs. The

treated sites were not wrapped; the volunteers were instructed not to wash the application site for 24 hours post

- treatment. Urine was collected at 4, 8, 12, and 24 hours post

- dose and each consecutive 24 hours for 5 days. Urine samples were brought to the laboratory for analy sis every 24 hours. In both experiments, the samples were collected in polystyrene or polypropylene containers, and 24

- hour samples were stored frozen until assayed for radioactivity using liquid scintillation counting.

Monkeys eliminated 43.5

- 51.5% of the administered radioactivity in the urine within 24 hours post

- dose and 52.3

- 72.3% (average 58.6%) within 7 days post

- dose. Following dermal application to humans, total urinary excretion of the applied doses was 0.052

- 0.702% (corrected for incomplete urinary excretion with a rhesus monkey parenteral excretion factor of 58.6%). This result suggests that the compound was poorly absorbed through the skin in humans. Peak excretion occurred during the first 24 hours post

- dose. Differences in absorption d ue to application site were not noted.

These are special studies and guidelines for the conduction of metabolism and dermal penetration studies were unavailable at the time this study was conducted. Insufficient reporting of methodology and the use of l ess than optimal procedures (such as not covering of the application site) suggest these data are useful for only supplementary

purposes.

This study is classified as acceptable/non

- guideline

.Page 54 of 54

APPENDIX C. Physical/Chemical Properties

Physicochemical Properties of Technical Grade Paraquat Dichloride.

Parameter Value Reference

Melting point/range decomposes at ca. 340 °C Product Chemistry Chapter of the Paraquat Dichloride Update, 10/10/91 pH 6.4 at 20 °C

Density 1.5 g/cm 3 at 25 °C

Water solubility (20 °C) freely soluble in water:

618

- 620 g/L at pH 5.2, 7.2, and 9.2

Solvent solubility (20 °C) <0.1 g/L in acetone, dichloromethane, toluene, ethyl acetate, and hexane; 143 g/L in methanol

Vapor pressure <<10

- 8 kPa at 25 °C

Octanol/water partition coefficient, Log(K OW ) log K OW =

- 4.5 at 20 °C

Dissociation constant, pK

a 0.95 (pure active ingredient) Product Chemistry Chapter of the Paraquat Reregistration Standard,

11/25/85

APPENDIX D. Studies Reviewed for Ethical Conduct

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task Force members Health Canada, U.S. Environmental Protection Agency, and the National Agricultural Chemicals Association, released February, 1995.

Agricultural Re

- ent ry Task Force (ARTF) data base (SOP #3.1)

MRIDs 00126097, 00126098, & 00126099. Kelly Sherman Human Research Ethics Reviewer, OPP, June 11, 2012.