OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION 

MEMORANDUM 

December 17, 2012 

TXR#:0056481 

SUBJECT: Quizalofop (quizalofop-ethyl and quizalofop-p-ethyl): Summary of Hazard 

and Science Policy Council (HASPOC) Meeting of October 4, 2012: 

Recommendations on the Requirement of the Neurotoxicity Battery and a 

Subchronic Inhalation Toxicity Study. 

PC Code: 128709, 128711 

Decision No.: N/ A 

Petition No.: N/A 

Risk Assessment Type: N/ A 

TXR No.: 0056481 

MRID No.: N/A 

DP Barcode: N/A 

Registration No.: Nl A 

Regulatory Action: N/ A 

Case No.: N/A 

CAS No.: NIA 

40CFR:N/A 

FROM: Kristin Rury, MPH ¥-~ Executive Secretary, HAS~oW Health Effects Division (7509P) 

~a-.~ THROUGH: Jess Rowland, Co-Chair ~~ I_/ 

Anna Lowit, Ph.D., Co-Chair ~ 

HASPOC 

Health Effects Division (7509P) 

TO: William Irwin, PhD, DABT, Toxicologist 

Danette Drew, Chemist 

Michael Metzger, Branch Chief 

Health Effects Division (7509P) 

MEETING ATTENDEES: 

HASPOC Members: Anna Lowit, Elissa Reaves, Jeff Evans, Jess Rowland, John Kough, Julie 

Van Alstine, Kristin Rury, Michael Metzger, PV Shah, Ray Kent 

Presenters: William Irwin, Danette Drew 

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I. PURPOSE OF MEETING: 

Quizalofop-ethyl is a 50150 racemic mixture ofR- and S-enantiomers, quizalofop-p-ethyl is the 

purified R-enantiomer, which is the pesticidally active isomer. HED had detennined that the 

toxicological profile of the 50/50 racemic mixture (quizalofop-ethyl) and the R-enantiomer 

(quizalofop-p-ethyl) are similar, and that the currently available toxicity and residue data on 

quizalofop-ethyl are adequate to support risk assessments reflecting either quizalofop-ethyl or 

quizalofop-p-ethyl. The two compounds may be collectively referred to as "quizalofop" in this 

document. In accordance with the revised 40 CFR Part 158 Toxicology Data Requirements, 

acute and subchronic neurotoxicity studies are required for quizalofop-ethyl and quizalofop-pethyl. A 28-day inhalation toxicity study in rats is also required due to the potential for repeated 

inhalation exposure to quizalofop-ethyl and quizalofop-p-ethyL The Hazard and Science Policy 

Council (HASPOC) met on October 4, 2012 to discuss the need for need for the acute and 

subchronic neurotoxicity studies, and a subchronic inhalation toxicity study to support registered 

uses of quizalofop. 

II. SUMMARY OF USE PROFILE & PREVIOUS RISK ASSESSMENT: 

Quizalofop-ethyl and quizalofop-p-ethyl are selective herbicides used for the control of annual 

and perennial grasses in a variety of crops and non-croplands (rights-of-way, fencerows, etc). 

There are no residential uses. They can be applied using ground and aerial equipment as 

broadcast and banded applications. All products are formulated as an emulsifiable concentrates 

(EC). Quizalofop-ethyl is a 50/50 racemic mixture ofR- and S-enantiomers. Quizalofop-p-ethyl 

is the purified R-enantiomer, which is the pesticidally active isomer. All of the currently 

registered products are formulated as the R-enantiomer. HED had determined that the 

toxicological profile of the 50/50 racemic mixture (quizalofop-ethyl) and the R-enantiomer 

( quizalofop-p-ethyl) are similar, and that the currently available toxicity and residue data on 

quizalofop-ethyl are adequate to support risk assessments reflecting uses of either quizalofopethyl or quizalofop-p-ethyL The two compounds may be collectively referred to as "quizalofop" 

in this document. . 

In the most recent human health risk assessment (I. Negr6n-Encarnaci6n, D384660, 11/17/2011), 

an oral point of departure (POD) was used for assessing risk via dietary (food and drinking 

water) exposure. The POD was based on increased incidence of centrilobular enlargement of the 

liver in both sexes of rats and mild anemia in male rats seen at the lowest observed adverse effect 

level (LOAEL) of3.7 mglkglday (no observed adverse effect level; NOAEL = 0.9 mg/kg/day) 

from the rat chronic toxicity/carcinogenicity study. There were no effects observed in oral 

toxicity studies that could be attributable to a single-dose exposure. Hence, a dose and endpoint 

have not been selected for assessment of acute exposure. Similarly, there was no observed 

toxicity in a dermal sub-chronic study at the highest dose tested (above the limit dose) so no 

dermal risk assessment was conducted. A chronic reference dose (cRfD) was established based 

on liver effects and decreases in body weight gain observed in a combined chronic 

toxicity/carcinogenicity study in rats. Mutagenicity studies conducted on quizalofop-ethyl did 

not demonstrate evidence of mutagenic potential. Quizalofop-ethyl is Category D, not 

classifiable as to human carcinogenicity. As such, a cancer risk assessment was not conducted. 

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The chronic dietary exposure and risk estimate utilized 11% of the chronic population adjusted 

dose (cPAD) for the general U.S. population, and 29% of the cPAD for children 1-2 years old, 

the highest exposed population subgroup. Occupational inhalation exposure assessments were 

originally not performed for quizalofop. However, as a screening analysis of occupational 

inhalation exposure, HED calculated inhalation risk estimates using the POD from the rat 

chronic toxicity/carcinogenicity study (NOAEL:::: 0.9 mglkglday) as a conservative exposure 

estimate. The occupational inhalation margins of exposure (MOEs) ranged from 2,900 to 

211 ,000. The level of concern (LOC) for the screening assessment would be an MOE < 100. 

III. STUDY WAIVER REQUESTS 

A. Inhalation Study 

Previously, the Office of Pesticide Programs (OPP) used a set of criteria to determine whether or 

not an inhalation study could be waived. These criteria considered the scientific information 

available for the chemical, including its: 1) degree of irritation and corrosivity; 2) volatility; 3) 

aerosol particle size; and 4) Acute Toxicity Category and extrapolated MOEs (e.g., MOEs 10 

times higher than the target). In 2009, OPP developed an issue paper on risk assessment 

approaches for semi-volatile pesticides. As part of that issue paper, an analytical comparison 

was conducted of oral and inhalation experimental toxicology studies. In general, this analysis 

showed that the degree to which oral point of departures (PODs) were protective of potential 

inhalation toxicity varied. In many cases the oral POD was protective, but in some cases the 

inhalation PODs were significantly more protective. Currently, OPP uses a weight of the 

evidence (WOE) approach that builds upon OPP's experience using the criteria listed above and 

conclusions from the 2009 SAP. As approaches for route-to-route extrapolation continue to 

evolve and improve, OPP may incorporate additional considerations into the WOE analysis. 

Inhalation exposure can be to vapors, droplets, and/or particles/dusts. The form of inhalation 

exposure is determined by a nwnber of factors including physical-chemical properties, use 

pattern, and exposure scenarios. OPP's interim WOE approach considers: 

l. Physical-Chemical Properties: Consideration of vapor pressure and the Henry's law 

constant are essential in assessin~ volatilization after sprays have settled. The vapor 

pressure of quiz.alofop is 8.3x10- 0 nun Hg 20 °C, The Henry's law constant is 1.1X10-8 

atm-cu m/mol at 20 °C. However, low vapor pressure and/or Henry's law constant does 

not preclude exposure to aerosolized droplets or particles/dusts. 

2. Use Pattern & Exposure Scenarios: Any application scenario that leads to inhalation 

exposure to droplets needs to be considered in the WOE analysis for an inhalation 

toxicology study waiver request. Air blast and aerial applications are more likely to lead 

to higher occupational handler inhalation exposure, particularly to droplets; and may also 

contribute to spray drift. Quizalofop may be applied with aerial or airblast equipment. In 

the case of quizalofop, mixing/loading for aerial application to cotton results in the 

highest inhalation exposure. 

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3. Margins of Exposure: The MOE estimates for inhalation scenarios were calculated using 

an oral toxicity study and should be considered in the WOE analysis for an inhalation 

toxicology study waiver request. In the past, OPP has used MOEs of approximately 10 

times higher than the LOC as a benchmark for granting waiver requests. The 2009 

analysis suggests this approach is appropriate for most pesticides, but not all. Under the 

interim WOE approach, MOEs from 1 0·1 00 times greater than the level of concern will 

be considered in combination with other factors discussed here. In the case of 

quizalofop, the inhalation MOEs for occupational handlers range from 2,900 to 211,000 

and meet the waiver criterion of MOEs ranging from 1 0·1 00 times the LOC. 

Toxicological Effects: Quizalofop-ethyl and quizalofop-p-ethyl are considered to be 

toxicologically similar. HED based this determination on a comparison of toxicity data 

submitted for the registration of quizalofop-ethyl and a subset of toxicity data for 

quizalofop-p-ethyl. Specifically, toxicity data available for quizalofop-p-ethyl included: 

an acute oral study in the rat, 90-day subchronic feeding studies in the rat and mouse. and 

three mutagenicity studies. Results from these studies were similar to results obtained 

from the same studies using quizalofop-ethyl. Conclusions regarding the toxicity of 

quizalofop-ethyl are applicable to quizalofop-p-ethyl. Quizalofop has low acute toxicity 

via the oral (Toxicity Category III), dermal (Toxicity Category IV), and inhalation routes 

(Toxicity Category IV) routes. It is not an eye or dermal irritant nor a skin sensitizer. 

Following oral administration, quizalofop-ethyl is rapidly absorbed and excreted via 

urine and feces. The liver is the primary target organ as evidenced by increased liver 

weight and histopathological changes. Liver effects and decreases in body weight gain 

and food consumption as a result of repeat dosing were seen in sub-chronic and 

chronic/carcinogenicity studies in rats, mice, and dogs. Developmental studies in rats 

and rabbits and a two-generation reproduction study in rats showed no evidence 

(qualitative or quantitative) for increased susceptibility following in utero and/or 

pre/post-natal exposure to quizalofop ethyL 

For considering a waiver request for an inhalation toxicity study, the Agency will 

evaluate other pesticides which share the same mode of action (MOA) and/or are in the 

same class. These pesticides can provide important information with respect to potential 

inhalation toxicity. Specifically, if other similar pesticides show inhalation toxicity 

studies to be more sensitive, an inhalation toxicity study may be required regardless of 

MOE, depending on the exposure profile. The ISTEP database did not indicate any 

inhalation endpoints based on specific inhalation studies for any of the related 

arylphenoxypropionate herbicides which inhibit acetyl~CoA carboxylase. There are no 

multi-day inhalation studies available for the following similar chemicals: fluazifop-Pbutyl, cyhalofop-butyl, diclofop-methyl, haloxyfop-R·methyl, and propaquizafop. 

In a fenoxprop-P·ethyl 28·day inhalation study, the main target organ was the liver 

(organ weight changes, effects in lipid metabolism), with effects being more pronounced 

in males than in females. Increased absolute (all dose groups) and relative (0.07 mg/L 

and above) liver weights were recorded. Effects on lipid metabolism were evident at 0.3 

mg!L. Furthermore, slight changes were noted in hematology at 0.07 mg/L and greater. 

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Another target organ of fenoxaprop-P-ethyl was the kidney, with increases in absolute 

and/or relative organ weights observed in both sexes at 0.3 mg/L. In conclusion, the 

NOAEL is considered to be 0.015 mg/L or 2.7 mglkg/day. The hazard component of 

chronic risk was the NOAEL of0.25 mglkg/day based on decreased total blood 

lipids/cholesterol at the LOAEL of 1.5 mglkg/day in a rat reproductive toxicity study. 

Based on a WOE approach consi~ering all the available hazard and exposure information 

for quizalofop, the HASPOC determined that a 28-day inhalation toxicity study in the rat is 

not required at this time. This approach considered all the available hazard and exposure 

information for quizalofop, including: (I) the low vapor pressure of quizalofop (8.3 X w-tO mm 

Hg); (2) the low acute inhalation toxicity of quizalofop (Toxicity Category IV); and (3) the use 

of an oral POD established for the most sensitive endpoint/target organ system resulting in 

screening-level MOEs ranging from 2,900 to 211,000. 

B. Neurotoxicity studies 

Acute and sub-chronic neurotoxicity studies are required in the 2007 revised 40 CFR Part 158 

Toxicology Data Requirements because they provide important scientific information on 

potential nervous system effects from pesticide exposure. These studies can provide data on a 

wide range of functional tests for evaluating neurotoxicity including sensory effects, 

neuromuscular effects, learning and memory and histopathology of the nervous system. 

Quizalofop did not show clear signs of neurotoxicity following acute, sub-chronic or chronic 

dosing in multiple species in the database. However, the existing guideline studies are inadequate 

in their assessment of behavioral effects and do not use optimal methods to evaluate the potential 

toxicity to nervous tissue structure and function. With respect to considering whether an acute or 

sub-chronic neurotoxicity study should be required for quizalofop, the HASPOC used the 

following weight of the evidence (WOE) approach: 

1. Evidence for neurotoxicity in the quizalofop database oftoxicology studies: 

The current toxicology database shows no clear evidence for neurotoxicity. The target 

organs are the liver and the testis. Other toxicity signs are apical, such as decreased body 

weight, decreased body weight gain or decreased food consumption. 

2. Evidence for neurotoxicity in the database of other similar chemicals: The pesticidal 

mode of action of quizalofop is by inhibiting acetyl CoA carboxylase (ACC, a key 

enzyme in plant fatty acid synthesis and required for maintaining membranes in 

functioning condition). The ACC inhibitors generally target the liver, kidney, or testes. A 

search of the !STEP database did not indicate neurotoxicity concerns for similar 

chemicals, including diclofop-methyl, fenoxaprop-ethyl, and fluazifop acid. 

Another ACC inhibitor, cyhalofop-butyl, had a NOAEL of2000 mg/kg in the acute 

neurotoxicity study, with no LOAEL identified. In the subchronic neurotoxicity study, 

the NOAELs were 75 mglkg/day in males and 250 mg/kg/day in females, with no 

LOAELs identified. In comparison with quizalofop, the risk assessment POD for chronic 

dietary exposure to cyhalofop-butyl is at a much lower dose: 0.99 mglkg/day derived 

from the chronic mouse study. 

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Another ACC inhibitor, fluazifop-P-butyl, showed no evidence of neurotoxicity but did 

exhibit liver and the testis as the target organs, similar to quizalofop. 

Based on a WOE approach, the HASPOC concluded that acute and subcbronic 

neurotoxicity studies are not required at this time. This approach included the following 

considerations: 1) there was no evidence of neurotoxicity or neuropathology in the available 

toxicology studies for quizalofop; 2) liver is the target organ and the oral POD is based on 

hepatotoxicity providing the most sensitive endpoint; 3) neurotoxicity studies in rats is unlikely 

to provide a more sensitive endpoint or a lower POD for risk assessment; and 4) the low concern 

for neurotoxicity in other members of this class of chemicals. 

IV. HASPOC RECOMMENDATIONS: 

Based on a WOE approach and considering all of the available quizalofop hazard and exposure 

information, the HASPOC concludes that a 28-day inhalation toxicity, acute neurotoxicity, and 

subchronic neurotoxicity studies are not required at this time. 

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