### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICA L SAFETY AND

POLLUTION PREVENTION



### MEMORANDUM

DATE: 5-MAR-2014



### SUBJECT : Imazapyr, Isopropylamine Salt : Registration Review Seeping

Document for Human Health Assessment.



### PC Code : 128821 and 128829


### Decision No.: 486732 

### DP Barcode: D 417328 

### Registration No. : 172267


### Petition No .: NA 

### Regulatory Action: Registration Review


### Case No .: 3078 

### Risk Assessment Type : Single

Chemical / Aggregate



### TXRNo.: NA



### MRIDNo.: NA 

### CAS No .: 81334-34-1, 81510

- 83-0


### 40 C FR: §180.500



### FROM: Mohsen Sahafeyan, Chemist and 

# Risk&s

. sessok : ! J

# LJ4y-**'** Nancy McCarro ll

, Toxi co l ogist 

### /tl

### ~ 

## ltc**":::"vu--- ~**  Bridgett Bobowiec, Bio logis t

### ~**~ ~**  Risk Assessment Branch VI (RAB VI)

Health Effects Division (HED, 7509P)

Office of Pesticide Programs



### THROUGH: Donna Davis, Acting Branch Chief

# ~ Registration Action Branch 6 (RAB6)

He alt h Effects Division (H E D, 7509P)



### TO : Joel Wolf, Chemical Review Manager

Tom Myers, Team Leader

Risk Management and Implementation Branch 4

Pesticide Re- E valuation Division (7508P)



### Executive Summary

The Health E ffects Division (HED) imazapyr Regi stration Review Team has eval uat ed

t he status of the human health risk assessment for imazapyr (PC code: 128821)

, inclu d ing


### its isopropylamine sa l t (PC code : 1 2 8829) to determine the scope of work necessary to

support Re gistrat ion Review. In this document when referred to imazapyr, isoporpylamin sa l t is also in cl ud ed. Imazapyr is a systemic, non-selective herbicide used

Page 1 of 15for the pre- and pos t -e m ergence contro l of a broad rang e of terrestria l and aquatic weeds

. The most recent risk assessmen t for imazapyr was co mpl ete d in 2013 (M. Sahafeyan, e t. al., D3840 3 5

, Jul y 2, 20 1 3 ) to s upp ort imp ort tolerances wi th o ut U.S. regis tra t ion for

r es idues of ima zapyr on imidazolinon e- t o l e r a n t soybean of Cultivan ce ® Production Sys t em, rapeseed s ub g roup 20A

, sunflower su b g roup 20B and l entil.

The irnazap yr toxicology database is considered to be adequate and no additiona l studies

are required for registration r eview. T h e BASF tole rance request for imp orted

ge ne t i ca ll y- m odi fi ed soybean and crop g r oup 20A, 20 B and lentil triggered a r ev i ew of

t he imazapyr toxicity d atabase and e ndp oints for ri sk assessment. In Se pt embe r of2012

, the HED imazapyr rev i ew team called for a meeting of Hazard and Science Polic y Counci l (HASPOC) to revisit the toxicity of imazapyr and determin e whether a quantitativ e risk assess ment was needed. Afte r reviewing th e available tox i cology

database for im azapy r
, HASPOC concluded, with reasonable certainty that dietary

, occupational a nd r es id e nt ia l exposures to ima zapyr do not po se a s i gn ifi cant human

health risk and therefore

, risk assessments are not needed. This decision was based on th e fact that although there is pot en tial fo r expos ur e to irn azapy r and alt h ough the existing toxicology studies do n ot use doses up to t h e li mi t dose

, the available data are high quality and no hazard was identified from the toxic i ty stu d ies. No adverse effects were observed in the sub mi tted toxicological studies regardless of t he route of exposure or the

spe cies tested. T h erefo r e, a quan t ita t ive risk assessm ent is not r eq uir ed. F urther, a draft

r isk assessm en t will not be r e quired for re g i strat ion review.

B ec ause th e r e i s no ha za rd identified for im azapy r from to x icity stu di es a nd there are no risk concerns from exposu re to i mazapyr, an exe mption from the requ i rement of a tolerance would be ap pr o priate fo r im azapyr; however

, th e regulatory divis ion s may chose to l eave the tolerances as they are
, remove a ll tolerances, or remove tole r ances for

c rop s without any other intern at ional harmonization issues at their discretion.

Introduction

Imazapyr

, [ 2-[ 4 ,5- dihydro-4-methyl-4-(1-methy l ethyl) -5- oxo-lH-imidazol-2-yl] -3- pyridinecarboxylic acid] is a systemic

, non

- selective imidazolinone herbicide for pre

- and

p ost -em e r gence control of a broad range of weeds

, including terre st rial annual and perennial grasses
, broad -le aved h e rb s
, woody species, and riparian and emergent aquatic species. The structure, chemical name s, and othe r identifiers for imazapyr may be found

in Table lA and lB.

The imazapyr R e regi s tration E li gibility Deci sion Document (RED) was issued on June

14

, 2006. Th e a dd en dum t o t he 2006 RE D which contained the Age n cy ' s re v i sions to th e imazapyr 

### RED l abe l l angu age was i ssued on October 23, 2008. The most recent risk

assessment for ima zapy r was completed i n 2013 (M. Sahafeyan, et. al.

, 0384035, July 2

, 2013) to sup p ort import tole ran ces without U. S. regist ra tion for r esidues of imazapyr on imidazolinone

- tole r ant soybean o f Cu l tivance ® Production System, rapeseed subgr oup 20A, sunflower subgroup 20B and lentil.

P age 2 of 15

### Page 3 of 15

Imazapyr is formulated as a liquid, a wettable powder (in water soluble bags only), and a s

a granular. Terrestrial applications of imazapyr consist of ground and aerial spray s , as well as granular broadcast applications

. Aquatic applications of imazapyr can be made using the liquid formulated products. The herbicide

, imazapyr

, is an anionic, organic

acid that is non

- volatile and is both persistent and mobile in soil. Commercial formulations contain either imazapyr acid or the imazapyr isopropylamine salt, both of

which are dissolved in a water solution.

The mechanism of action of imidazolinone herbicides on weeds and non

- tolerant plants is by inhibition of the AHAS enzyme which is the key control enzyme for biosynthesis of

branched

- chain amino acids within plants. For genetically

- modified soybean (CV127)

, because the binding site for imidazolinone on AHAS enzyme is altered, there is a tolerance to imidazolinone herbicide while AHAS enzyme maintains its biosynthesis

function of branched

- chain amino acids.

Th 

### ere are currently twenty

- seven tolerances esta blished in 40 CFR §180.500 for residues of the herbicide imazapyr, applied as the acid or ammonium salt

. 

### Tolerances are established for imazapyr residues in field corn and its forage and stover, and in grass forage and hay. Import tolerances are establis hed for rapeseed subgroup 20A, s unflower subgroup 20B and lentil. An i mport t olerance on the imidazolinone

- tolerant soybean

from the Cultivance ® 

### Production System has also been recommended by HED (Sahafeyan, M., DP# D384035 and D403741; 7/2/2013)

. Tolerances are also established for secondary residues of imazapyr in m ilk, meat, fish, and shellfish. Imazapyr is also registered for use on a variety of commercial and residential use sites, including forestry sites, rights

- of

- way, fence rows, hedge row s, drainage systems, outdoor industrial areas, outdoor buildings and structures, domestic dwellings, paved areas, driveways, patios, parking areas, walkways, various water bodies (including ponds, lakes, streams, swamps, wetlands, stagnant water, and urban areas). Imazapyr may also be used as a spot treatment in recreation areas, athletic fields, and golf course roughs. T here are 1 1 Special Local Needs ( SLNs ) f

or imazapyr (including its isopropylamine salt) in states of AL, FL, HI, ME, ND, NM, SD, and TX.

Hazard Identification/Toxicology

The toxicological database for imazapyr is complete. Imazapyr is not irritating to the skin, and is negative for dermal sensitization; however, the technical grade (99.3% a.i.) of the active ingredient was tested for eye irritation and results in dicated irreversible eye damage (toxicity category I). The toxicity data show that there is no evidence of neurotoxicity, immunotoxicity, genotoxicity, or carcinogenicity for imazapyr

. Further, no adverse developmental effects or adverse reproductive effects were detected in well

conducted guideline studies.

The latest assessment of the toxicity database for imazapyr was conducted in September 2012 ( Imazapyr: Summary of Hazard and Sci ence Policy Council (HASPOC) Meeting of September 13, 2012: Recommendations on the type of risk assessment (quantitative vs. qualitative) to be conducted. TXR# 0056464, 2/26/13 )

. HASPOC considered whether a quantitative risk assessment was necessary for imazapyr. B ecause there is no hazard

### Page 4 of 15

identified for imazapyr in the available database ( i.e., no toxicity demonstrated in acceptable guideline studies generally up to the highest doses tested of 250

– 1000 mg/kg/day) , the HASPOC concluded that a quantita tive risk assessment was not required for imazapyr . Since July 2005, when the most recent Reregistration Eligibility Document (RED) for Imazapyr was prepared (Jarvis et al., 2005), no new data have been received that would warrant a change in the acute or chronic reference doses (RfDs), the occupational/residential toxicological endpoint selections, the uncertainty factors, or the FQPA Safety Factor.

Dietary Exposure

The current residue chemistry database is sufficient to support the registration review of imazapyr. No additional residue chemistry studies are needed. H owever, if in the future imazapyr use on additional GM crops or the same crops with different types of genetic

modifications are sought , adequate ratio nal and information should be provided to show that the metabolic pathway s in non

- tolerant and tolerant plants are comparable.

No dietary hazar d was identified in the imazapyr toxicity database. Becaus e imazapyr does not pose a dietary (food and drinking water) risk, a quantitative dietary risk assessment is not required. Consequently, an updated or revised dietary risk assessment will not be required for registration review.

Residential (Non

- Occupational) Exposure

The current occupational and residential database is sufficient to support the registration review of imazapyr. No additional studies are needed.

No hazar d was identified in the imazapyr toxicity database ; eye irritation issue is addressed in the occupational section below . Be cause imazapyr does not pose a

residential risk, a quantitative dietary risk assessment is not required. Consequently, an updated or revised occupational and residential risk assessment will not be required for registration review.

Aggregate Exposure and Risk

HASPOC in September 2012 determined that there is no hazard identified in the toxic studies for imazapyr and concluded with reasonable certainty that dietary, occupational

and residential e xposures to imazapyr do not pose a significant human health risk and, therefore, quantit ati ve risk assessments , including aggregate risk assessments are not
needed

.

Occupational Exposure

The current occupational and residential database is sufficient to support the registration

### Page 5 of 15

review of imazapyr. No additional studies are needed.

No hazard was identified in the imazapyr toxicity database. Because imazapyr does not pose an occupational risk, a quantitative dietary risk assessment is not required.

Con sequently, an updated or revised occupational and residential risk assessment will not be required for registration review. However, because of toxicity category for primary eye irr i tation for technical grade imazapyr

, HED recommends that the requirements for personal protective equipment (PPE) on en d

- use products for o ccupational handler and

post

- application exposure be re

- reviewed. Requirement for p rotective eyewear should

appear on all labels of end

- use products that are toxic category I for eye irrita tion. Application to non

- c rop areas such as rights

- of

- way is not bound by worker pr otection

standards (WPS) . I mazapyr end

- use products that are currently registered for corn should

retain a restricte d ent ry interval (REI) of 48 hours for post

- application workers

.

P ublic Health and Pesticide Epidemiology Data

OPP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System for Occupational Risk

- Pesticides (SENSOR) databases were consulted for pe sticide incident data on the active ingredient Imazapyr (PC codes: 128821

and 128829 ). The purpose of the database search is to identify potential patterns in th e frequency and severity of the health effects attributed to Imazapyr exposure. Agricultural Health Study (AHS) was not consulted as imazapyr is not included in that study.

Based on the low severity and relatively low frequency of incident cases reported for imazapyr in both IDS and SENSOR

- Pesticides, there does not appear to be a concern at this time that would warrant further investigation. Ortho® GroundClear® Vegetation

Ki ller Concentrate (Reg No 239

- 2657) does appear to be implicated in a disproportionate amount of incidents which may be attributable to high use of this product by consumers. Ortho® GroundClear® Vegetation Killer Concentrate is a co

- formulated product, whi ch in addition to imazapyr (0.8%), also contains the active ingredient glyphosate (5%). This may be potentially attributable to the high use of this product by consumers. ( Recore, Shanna, D417421 , 1/25/2014 )

Tolerance Assessment and International Harmon ization

U

. S

. permanent tolerances for imazapyr are listed in 40 CFR 180.500 and are

summarized in Table 2.

Canadian Maximum Residue Limits (MRLs) are established for a variety of agricultural crops, as well as in livestock commodities. There are no Codex or Mexican MRLs established for imazapyr.

Because there is no hazard identified for imazapyr from toxicity studies and there are no risk concerns from exposure to imazapyr, an exemption from the requirement of a tolerance would be appropriate fo r imazapyr; however, the regulatory divisions may

### Page 6 of 15

chose to leave the tolerances as they are, remove all tolerances, or remove tolerances for crops without any other international harmonization issues at their discretion. Should the regulatory division choo se to harmonize with Canada, the following section details HED

recommendation s

.

The Canadian residue definition is the same as that of U. S. The current U.S. tolerances

are harmonize d with Canadian MRLs with respect to the level of regulation except fo r the kidney of ruminants . Canada does not have a separate tolerance for residues on imazapyr in kidney of ruminants, instead it is covered under meat byproducts MRLs at 0.05 ppm. However, there are separate US tolerances for kidney (at 0.2 ppm) and meat byproducts, except kidney (0.05 ppm). HED recommends that separate US tolerance for kidney be revoked and “meat byproduct, except kidney” be changed to “meat byproducts” (at 0.05 ppm) to harmonize with Canadian MRLs according to the following table.

Com modity US Tolerance

(ppm) Canada Proposed US

Tolerance Cattle, kidney 0.2 0.05 meat byproducts of

cattle revoke

Cattle, meat byproducts, except kidney 0.05 0.05 meat byproducts of

cattle change the

commodity

definition to: Cattle, meat byproducts
Goat, kidney 0.20 0.05 meat byproducts of

goat revoke

Goat, meat byproducts, except kidney 0.05 0.05 meat byproducts of

goat change the

commodity

definition to: Goat, meat byproducts Horse, kidney 0.20 0.05 meat byproducts of

horse Revoke

Horse, meat byproducts, except kidney 0.05 0.05 meat byproducts of

horse change the

commodity

definition to:
Horse, meat byproducts Sheep, kidney 0.20 0.05 meat byproducts of sheep Revoke

Sheep, meat byproducts, except kidney 0.05 0.05 meat byproducts of sheep change the

commodity

definition to: Sheep, meat byproducts

### Page 7 of 15

There are also commodities with US tolerances for which there are no Canadian MRLs. The regulatory division may, as the registration review for imazapyr progresses , revoke

all those tolerances to harmonize with Canadian MRLs.

International or Intergovernmental Work Sharing

HED is not currently involved in any joint international review projects that involve the active ingredient, imazapyr. Additionally, HED is unaware of any ongoing international assessments for imazapyr. Given the lack of toxicity for this chemical and the lack of any identified new work, HED has not identified any potential work sharing opportunities for imazapyr.

Cumulative Risk Assessment

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to imazapyr and any other substances and imazapyr 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 imazapyr has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine

which che micals 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 f rom substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

Data Requirements

None

References

Author Barcode Date Title

P. Yvonne

Barnes D320579 08/29/2005 Imazapyr: Summary of Product Chemistry Data for Reregistration Eligibility Decision (RED) Document.

William

Donovan D288806 3/26/2003 Imazapyr. Chronic Dietary Exposure Assessment for the Section 3 Registration Action on Grasses and Aquatic Sites.

Christina Jarvis,

et.al. D324106 8/12/2005 Imazapyr: Revised HED Chapter of the Reregistration Eligibility Document (RED).

Kristin Rury TXR#

0056464 2/26/13 Imazapyr: Summary of Hazard and Science Policy Council (HASPOC) Meeting of

### Page 8 of 15 September 13, 2012: Recommendations on

the type of risk assessment (quantitative vs. qualitative) to be conducted.

Mohsen Sahafeyan,

et.al. D384035,

D403741 7/2/2013 Imazapyr: Petition for the Establishment of Import Tolerances on Genetically

- Modified (GM) Soybean, Rapeseed subgroup 20A, Sunflower Subgroup 20B and Lentils

Charles

Smith D320582 08/31/ 2005 Imazapyr: Occupational and Residential Exposure Assessment for the Reregistration Eligibility Decision Document

Shanna

Recore D417421 1/25/2014 Imazapyr : Tier I Review of Human Incidents

Table 1A

- Chemical Identity of Imazapyr

Chemical structure

Common name Imazapyr

Company experimental name BAS 693 H

IUPAC name 2

- [( RS )

- 4

- isopropyl

- 4

- methyl

- 5

- oxo

- 2

- imidazolin

- 2

- yl]nicotinic acid

CAS name 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- imidazol

- 2

- yl]

- 3

- pyridinecarboxylic acid

CAS registry number 81334

- 34

- 1

End

- use product (EP) Not Specified

Table 1B

- Physicochemical Properties of Imazapyr

Parameter Value Reference

Melting point 169

- 173°C DP# 324106, C. Jarvis et al.,

12/08/05 pH 2.5 at 25°C

Density 0.35 g/mL

Water solubility 1.11 g/100 mL

Solvent solubility NA

Vapor pressure <2 x 10
- 7 mm Hg at 25°C

Dissociation constant, pK

a pk 1 = 1.9, pk 2 = 3.6

Octanol/water partition coefficient, Log(K OW ) 1.3 at 22°C

UV/visible absorption spectrum NA

### Page 9 of 15

Table 2

- Summary of US and International Tolerances and Maximum Residue

Limits
Residue Definition :
US Canada Mexico 2 Codex

40 CFR 180.500

imazapyr [2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1H

- imidazol

- 2

- yl]

- 3

- pyridinecarboxylic acid] 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

imidazol

- 2

- yl]

- 3

- pyridinecarboxylic acid None



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

US Canada Mexico 2 

### Codex

Cattle, fat 0.05 0.05 Cattle, kidney 0.20 0.05 meat byproducts of cattle
Cattle, meat 0.05 0.05 Cattle, meat byproducts, except kidney 0.05 0.05 meat byproducts of cattle

Corn, field, forage 0.05 Corn, field, grain 0.05
Corn, field, stover 0.05

Fish 1.0
Goat, fat 0.05 0.05 Goat, kidney 0.20 0.05 meat byproducts of goat
Goat, meat 0.05 0.05 Goats, meat byproducts, except kidney 0.05 0.05 meat byproducts of goat

Grass, forage 100 Grass, hay 30
Horse, fat 0.05 0.05 Horse, kidney 0.20 0.05 meat byproducts of horse
Horse, meat 0.05 0.05 Horse, meat byproducts, except kidney 0.05 0.05 meat byproducts of horse

Lentil 1 0.2 0.2 dry lentils

Milk 0.01 0.01 Rapeseed subgroup 20A 1 0.05 0.05 seeds (borage, cuphea, echium, flax, gold of pleasure, hare's ear mustard, milkweed, mustard seed (oilseed type), oil radish, poppy, rapeseed (canola), sesame, sweet rocket Sheep, fat 0.05 0.05 Sheep, kidney 0.20 0.05 meat byproducts of sheep Sheep, meat 0.05 0.05 Sheep, meat byproducts, except kidney 0.05 0.05 meat byproducts of sheep

Shellfish 0.10 Sunflower subgroup 20B 1 0.05

MRLs with NO US Equivalent Eggs 0.05 Fat of hogs 0.05 Fat of poultry 0.05

M eat byproducts of hogs 0.05

### Page 10 of 15

M eat byproducts of poultry 0.05

M eat of hogs 0.05

M eat of poultry 0.05

Completed: M. Negussie; 1/08/2014

1 There are no U.S. Registrations

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



### Table 3

- Summary of Maximum Application Rates for Registered Imazapyr Commercial Uses

Crop Type/Use Site Target of Application Application Equipment Maximum Application

Rate

non

- crop areas (including highway rights

- of

- way, turfgrass (recreation areas, athletic fields, golf course roughs, commercial/ industrial areas) grasses, weeds, paved surfaces aerial, groundboom, low

- pressure handwand, high

pressure handwand, handgun, rights

- of

- way sprayer, backpack 1.5 lb ai/A (liquid)

non

- crop areas (including highway rights

- of

- way, turfgrass (recreation areas, athletic fields, golf course roughs, commercial/ industrial areas) grasses, weeds aerial, tractor drawn spreader, push

- type spreader, backpack spreader 1.5 lb ai/A (granular)

broadcast application to aquatic areas or

draw down area aquatic vegetation aerial, boat, handgun, low

- pressure handwand 1.5 lb ai/A

trees brush, trees aerial, groundboom, handgun, rights

- of

- way sprayer 1.25 lb ai/A

areas grazed or cut for hay saltcedar aerial, groundboom, low

- pressure handwand 1.0 lb ai/A

trees brush, trees EXJECT capsule injection equipment

- -



### Table 4

- Summary of Maximum Application Rates for Registered Imazapyr Residential Uses

Crop Type/Use Site Target of Application Application Equipment Maximum Application

Rate

driveways, parking areas, brick walls, gravel pathways, patios, along sidewalks and bare

ground grasses, weeds low

- pressure handwand, sprinkling can 0.19 lb ai/1,000 sq ft



### Table 5

- Status of Required Toxicological Studies for Imazapyr

Guideline Numbers

(Note: Use of the new guideline numbers does not imply that the new
(1998) guideline protocols were used) Technical

Required Satisfied 1

870.1100 Acute Oral Toxicity

................................ ................................ . 870.1200 Acute Dermal Toxicity

................................ ............................. 870.1300 Acute Inhalation Toxicity

................................ ........................ 870.2400 Primary Eye Irritation

................................ .............................. 870.2500 Primary Dermal Irritation

................................ ......................... 870.2600 Dermal Sensitization

................................ ................................ yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

### Page 11 of 15

Table 5

- Status of Required Toxicological Studies for Imazapyr

Guideline Numbers

(Note: Use of the new guideline numbers does not imply that the new
(1998) guideline protocols were used) Technical

Required Satisfied 1

870.3100 Oral Subchronic (rat and mouse)

................................ ............. 870.3150 Oral Subchronic (dog)

................................ .............................. 870.3200 21/28

- Day Dermal (rat)

................................ ............................ 870.3250 90

- Day Dermal

................................ ................................ ......... 870.3465 28

- Day Inhalation

................................ ................................ .... yes

yes

yes

no

no yes

yes

yes

---

---

870.3700a Developmental Toxicity (rat)

................................ ................... 870.3700b Developmental Toxicity (rabbit)

................................ .............. 870.3800 Reproduction (rat)

................................ ................................ .... yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rat)

................................ .............................. 870.4100b Chronic Toxicity (dog)

................................ ............................. 870.4200a Carcinogenicity (rat)

................................ ................................ 870.4200b Carcinogenicity (mouse)

................................ .......................... 870.4300 Chronic/Carcinogenicity (rat)

................................ .................. yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

................................ 870.5300 Mutagenicity

— Gene Mutation

- mammalian

........................... 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

.............. 870.5395 Mutagenicity

— Mammalian Erythrocyte Micronucleus

........... 870.5450 Mutagenicity

— Rodent dominant lethal assay 870.5500 Mutagenicity

— Bacterial DNA Damage or Repair Test
870.5550 Mutagenicity

— Unscheduled DNA Synthesis

............................. yes

yes

yes

yes

no

no

no yes

yes

yes

see footnote 1

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity. (hen)

................................ ........ 870.6100b 90

- Day Neurotoxicity (hen)

................................ ..................... 870.6200a Acute Neurotoxicity Screening Battery (rat)

............................ 870.6200b 90 Day Neurotoxicity Screening Battery (rat)

.......................... 870.6300 Developmental Neurotoxicity (rat)

................................ .......... no

no

yes

yes

no ---

--- yes

yes

see footnote 1

870.7485 General Metabolism (rat)

................................ ......................... 870.7600 Dermal Penetration

, in vivo (male rat)

................................ ..... yes

no yes

yes

870.7800 Immunotoxicity (rat and mouse)........................... yes see footnote 1

Non

- Guideline : Comparative dermal absorption, in vitro (rat

and human skin) no

--

1 According to the present HED policies, the toxicology database is considered to be adequate and no additional studies are required.
This is because, HASPOC confirmed that the available data do not suggest that there is a concern for neurotoxicity, i mmunotoxicity, genotoxicity, or carcinogenicity ( Imazapyr: Summary of Hazard and Science Policy Council (HASPOC) M eeting of September 13,

2012: Recommendations on the type of risk assessment (quantitative vs. qualitative) to be conducted. TXR# 0056464, 2/26/13).

### Page 12 of 15

Table 6

- Acute Toxicity of Imazapyr Technical Grade Active Ingredient (TGAI)

Guideline No/Study Type MRIDs Results Toxicity Category

870.1100 Acute Oral 41551002 (1990) 93048016 (1990) LD 50 = > 5000 mg/kg IV

870.1200 Acute Dermal 41551003 (1990) 93048017 (1990) LD 50 = >2000 mg/kg III

870.1300 Acute Inhalation

TXR# 0006998 00132032 (1983) 93048018 (1990) LC 50 = >1.3 mg/L (gravimetric) > 5.1 mg/L (nominal) III

870.2400 Primary Eye Irritation/NZW rabbit 41551001 (1990) 93048019 (1990) 2/6 rabbits with corneal opacity at

21 days; discharge in 1/6 rabbits at 21 days; vascularization of cornea in 1/6 rabbits at 21 days;

Irreversible Eye Damage I

Tested with 99.3% technical fine powder

870.2400 Primary Eye Irritation/NZW rabbit Accession# 252004 Corneal opacity cleared within 72 hours; conjunctivitis reversible by

day 7 III

Tested with 93%

technical

870.2500 Primary Skin Irritation 41551004 (1990) 93048020 (1990) non

- irritating to slight erythema

and edema IV

870.2600 Dermal Sensitization 00131607 (1983) 93048021 (1990) Negative

-

Table 7

- Toxicity Profile of Imazapyr Technical.

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

Classification/Doses Results

870.3100

90

- Day oral toxicity rodents (rat) 42774401 (1992) Acceptable/guideline 0, 15,000, or 20,000 ppm (equivalent to 0, 1248, or 1695 mg/kg bw/day in males and 0, 1423 or 1784 mg/kg bw/day in females). NOAEL =1,695 mg/kg/day for males and =1,784 mg/kg/day for females (HDT).

LOAEL = None.

870.3200

21/28

- Day dermal toxicity (rabbi t) 00131609 (1983) 93048022 (1990) Acceptable/guideline 0, 100, 200 or 400 mg/kg/day, 6 hrs/day for 5 d/week during a 21

- day period. NOAEL =400 mg/kg/day (HDT).

LOAEL = None.

870.3700a Prenatal developmental toxicity

in rodents (rat) 00131611 ( 1983 )

93048023 (1990) Acceptable/guideline
0, 0, 100, 300 or 1,000 mg/kg/day from days 6 through 15 of gestation. Maternal NOAEL = 300 mg/kg bw/day. LOAEL =1,000 mg/kg bw/day, based on salivation.

Developmental NOAEL =1,000 mg/kg/day. This was the HDT; there fore, there is no LOAEL.

### Page 13 of 15

Table 7

- Toxicity Profile of Imazapyr Technical.

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

Classification/Doses Results

870.3700b Prenatal developmental toxicity

in non rodents (rabbit) 00131613 (1983) 93048024 (1990) Acceptable/guideline 0, 25, 100, or 400 mg/kg/day from days 6 through 18 of gestation. Maternal NOAEL =400 mg/kg bw/day This was the HDT; therefore, there is no LOAEL.

Developmental NOAEL =400 mg/kg bw/day. This was the HDT; therefore, there is no LOAEL.

870.3800 Reproduction and fertility

effects (rat) 41039505 (1987) Acceptable/guideline 0, 1,000, 5,000 and 10,000 ppm in the diet (equivalent to 0, 74.2, 380.5, or 738 mg/kg bw/day for males and 0, 94.3, 471.2, or 933.3 mg/kg bw/day for females). Parental systemic, reproductive and offspring NOAEL =10,000 ppm (738 mg/kg bw/day in males

933. 3 mg/kg bw/day in females). This was the HDT;

therefore, there is no LOAEL.

870.4100a Chronic toxicity (rodent) NA; see 870.4300 NA

870.4100b Chronic toxicity (dog) 41039502 (1987) Acceptable/guideline 0, 1,000, 5,000 or 10,000 ppm (equivalent to 0, 25, 125 or 250 mg/kg/day) for 1 year. NOAEL is =10,000 ppm (250 mg/kg/day)(HDT).

LOAEL. = None.

870.4200a Carcinogenicity (rat) NA; see 870.4300

870.4200b Carcinogenicity (mouse) 41038505 (1988) 42774401 (1992) Acceptable/guideline
0, 1,000, 5,000 or 10,000 ppm (equivalent to 0, 126, 674 or 1,301 mg/kg /day in males and 0, 151,776 or 1,639 mg/kg /day in females)

for 18 months. NOAEL =10,000 ppm (1,301 mg/kg/day in males and 1,639 mg/kg/day in females). This was the HDT; therefore, there is n o LOAEL.

870.4300 Combined Chronic/Carcinogenicity (Sprague Dawley rat) 41039503 (1988) Acceptable/guideline 1
0, 100, 5000, 10000 ppm (M/F: 0/0, 49.9/64.2, 252.6/317.6, 503/638.6 mg/kg/day) NOAEL = 10000 ppm (M/F: 503/638.6 mg/kg/day.

LOAEL = None was shown, however a statistically significant (but within normal range) increase in BUN and a nominal decrease in body weight gain in males (2%)(may have approached a toxic dose) and a nominal increase (not statistically significant, pair wise) in brain

ast rocytomas was seen in females, which the CARC classified as a “group E chemical”, no evidence of carcinogenicity in mice or rats. A 90

- day study in rats

### Page 14 of 15

Table 7

- Toxicity Profile of Imazapyr Technical.

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

Classification/Doses Results

showed no adverse effects at levels including the limit dose of 20,000 ppm (1000 mg/kg/day).

870.510 0

Bacterial reverse mutation (Ames Assay) 00131615 (1983) 93048025 (1990) Acceptable/guideline Negative up to 5,000 μg/plate.

870.5300

In vitro mammalian cell gene

mutation 00151641 (1984) 93048028 (1990) Acceptable/guideline Negative up to cytotoxic doses (5,000 μg/mL) with and

without activation.

870.5375

In vitro mammalian chromosome aberration (CHO) 00151640 (1984) 93048026 (1990) Acceptable/guideline Negative up to cytotoxic doses (5,000 μg/mL) with and

without activat ion.

870.5550 Unscheduled DNA synthesis

(RPH) 00151639 (1984) 93048027 (1990) Acceptable/guideline Reported as negative (unacceptable, 1989), but considered acceptable in 1997. 2

870.5450

Rodent Dominant Lethal 00151638 (1985) Acceptable/guideline Reported as negative (unacceptable, 1989), but considered acceptable in 1997. 2

870.6200a Acute neurotoxicity screening battery (rat) 48469001 (2011) Acceptable/guideline 0, 200, 600 mg/kg NOAEL =≥2000 MG/KG ( HDT); THEREFORE,

THERE IS NO LOAEL

870.6200b 90 Day neurotoxicity screening battery (rat) 48469001 (2011) Acceptable/guideline 0, 300, 1000 mg/kg/d (0, 89, 272, 924 mg/kg/d ♂; 0 92, 283, 933 mg/kg/d ♀) NOAEL ≥924 mg/kg/d (♂); ≥933 mg/kg/d (♀) (HDT);
therefore, there is no LOAEL

### Page 15 of 15

Table 7

- Toxicity Profile of Imazapyr Technical.

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

Classification/Doses Results

870.7485

Metabolism and pharmacokinetics (rat) 43861501 (1994) Acceptable

M&F: unlabeled or labeled imazapyr ~ 9.5 mg/kg or 924 mg/kg single gavage dose or

as 14

- daily doses of unlabeled imazapyr followed by single labeled dose of 9.26 mg/kg.

M&F: 10 mg/ kg labeled imazapyr single gavage dose

to measure excretion via expired air (pilot study).

M&F: 9.94 mg/kg labeled imazapyr by intravenous injection. No sex

- related differences in absorption were apparent.

Within 48 hours of treatment, >90% of the admini stered dose was recovered in the excreta suggesting that elimination of the labeled test material was rapid. No specific sequestering tissues or organs were identified. Seven days after treatment, essentially all the test

material had been eliminated. Rats that received the test material by intravenous injection excreted 87

- 95% of the administered dose in the urine and approximately 6% into the feces. This suggests that 15

- 28% if the oral administered dose recovered in the feces represents

unabsorbed m aterial.

Metabolite characterization studies show that essentially all of the test material was excreted unchanged. Two minor metabolites CL 252,974 and CL 60,032 were detected in the urine or feces of treated rats; however,

their contribution combined w as < 0.5% of the administered dose. Up to 12 additional unidentified metabolites were isolated, but they constituted <3% of the administered dose. Based on the results, the study author suggests that what limited metabolism of CL 243,997 occurs, proceeds through hydrolysis to form the

2

- carbonyl derivatives: CL 252,974 and CL 60,032.

870.7600 Dermal penetration NA NA

870.7800 Immunotoxicity 48490102 (2011) Acceptable/guideline 0, 500, 1500, 5,000 ppm (equivalent to 0, 155, 525 or 1,668 mg/kg /day in female

mice) NOAEL = ≥1,668 mg/kg/day; LOAEL was not

established.

1 The study is acceptable for regulatory purposes according to documentation in TXR# 0011692 (1995), TXR# 0051943 (2003), and TXR# 0011213 (1994).

2 Memorandum, dated 3/10/97, from Steve Robbins et al. of HED to Phillip Errico RD.