Page 2 of 7

Background

Cyantraniliprole is a second generation ryanodine receptor insecticide being jointly developed by 

DuPont and Syngenta. It is being reviewed as part of a global work share project. The crops 

proposed in the U.S. include berries, citrus, cotton, oilseeds, ornamentals, pome fruit, potatoes, 

stone fruit, tree nuts, turf, and various vegetables. Application methods include foliar spray, drip 

irrigation, soil drench and seed treatment. Metabolism studies were conducted on rice, cotton, 

tomato and lettuce as primary crops; lettuce, red beet, soybean and wheat as rotational crops;

laying hens and lactating ruminants. In addition, soil and aquatic metabolism studies under 

aerobic and anaerobic conditions, aqueous photolysis and hydrolysis studies, and terrestrial field 

dissipation studies were conducted to understand the environmental fate of cyantraniliprole.

Committee Recommendation

Table 1. Summary of Metabolites and Degradates to be included in the Risk Assessment 

and Tolerance Expression

Matrix Residues included in Risk 

Assessment1

Residues included in 

Tolerance Expression

Plants Primary Crop Cyantraniliprole Cyantraniliprole

Rotational Crop Cyantraniliprole Cyantraniliprole

Processed Commodities Cyantraniliprole and IN-J9Z38 Cyantraniliprole

Livestock Ruminant Cyantraniliprole, IN-N7B69, 

IN-MLA84, IN-MYX98,

and/or IN-J9Z382

Cyantraniliprole

Poultry Cyantraniliprole

Drinking Water Cyantraniliprole and the 

degradates listed below3

Not Applicable

1 Cyantraniliprole is 3-Bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-

carboxamide. The names and chemical structures of the metabolites can be found in Appendix 1.

2

Parent cyantraniliprole is recommended as residue of concern in all commodities along with the metabolites that are at 

significant amount in the commodity under consideration. 

3

IN-J9Z38, IN-NXX69, IN-QKV54, IN-RNU71, IN-JSE76, IN-JCZ38, IN-K5A78, IN-K5A77, IN-K5A79, and IN-PLT97. 

Summary of Briefing Materials Considered

Cyantraniliprole is an anthranilic diamide insecticide which acts through unregulated activation 

of ryanodine receptor (RyR) channels leading to calcium depletion and impaired regulation of 

muscle contraction. The major findings following repeated oral administration in rats, mice and 

dogs were changes in the liver, thyroid gland, and adrenal cortex. The thyroid toxicity observed 

was likely a result of increased hepatic enzyme activities and perturbation of the thyroid 

hormone homeostasis, and minor changes in the adrenal cortex were not considered biologically 

significant. Therefore, the primary mode of toxicity to mammals is hepatotoxicity. 

Cyantraniliprole was not observed to cause genotoxicity, neurotoxicity or immunotoxicity in rats 

and/or mice. No increase in tumor incidence was observed in adequately conducted 

carcinogenicity studies in rats and mice. Acute oral toxicity and mutagenicity studies are 

available for several metabolites including IN-JSE76, IN-PLT97, IN-F6L99 and IN-N5M09.

While the acute studies did not indicate significant increases in toxicity for any of the 

metabolites, the primary mode of action for cyantraniliprole, liver toxicity, is not likely to 

manifest after a single exposure. However, in a 28-day feeding study with IN-JSE76 in rats, no
Page 3 of 7

adverse effects were observed up to the highest dose tested (20,000 ppm, equivalent to1445 

mg/kg/day). Although this is still considered a short-term study, 28 days is sufficient to indicate 

potential hepatic injury. Therefore, assuming equal toxicity between parent and similarly 

structured metabolites/degradates is likely a conservative estimation.

Metabolism studies were conducted with cyantraniliprole radiolabeled in the cyano group or in 

the carbonyl adjacent to the pyrazole ring. The metabolism of cyantraniliprole applied to rice, 

lettuce, cotton and tomato were similar after foliar and soil applications; cyantraniliprole was the 

major residue in addition to the formation of many minor metabolites. Results in crop field trials 

confirm parent as the predominant residue.

In addition to parent cyantraniliprole, several residues have also been identified in processing 

studies. Nature of the residue in processing studies showed formation of degradates IN-J9Z38, 

IN-N5M09, and IN-F6L99 under conditions of heat and/or hydrolysis. Magnitude of the residue 

studies showed formation of these degradates in certain processed commodities. For example, 

IN-J9Z38 was present in cooked spinach, orange oil, tomato paste, cotton seed oil, and cotton 

seed meal. Indeed, most of the cyantraniliprole was degraded to IN-J9Z38 in cooked spinach. 

IN-N5M09 and IN-F6L99 were each about 1 - 2% of the IN-J9Z38 concentration in cooked 

spinach. All three degradates were generated in apple sauce, with IN-J9Z38 approximating the 

concentration of cyantraniliprole and IN-N5M09 and IN-F6L99 each being <10 - 20% of the

combined cyantraniliprole plus IN-J9Z38 concentration in the apple sauce. Degradates INN5M09 and IN-F6L99 were <LOQ (<0.01 ppm each) in commodities from processing studies 

with tomato, orange, plum, cottonseed, grapes, and olives.

In confined rotational studies, parent cyantraniliprole was the major residue present in soybean, 

wheat grain, lettuce, and beet root. Some metabolites were found at levels greater than 10% of 

the TRR only in livestock feedstuffs. In feedstuff commodities including wheat forage, hay, and 

straw, parent and IN-J9Z38 accounted for the majority of the residues. In soybean foliage, 

parent, IN-JSE76 and IN-MLA84 accounted for the majority of the residues. In field rotational 

crop studies, low levels of parent and metabolites were observed at the 30-day plant back interval 

except for animal feeds. In hay, forage, and straw of several crops, in addition to 

cyantraniliprole, significant amounts of metabolites such as IN-JCZ38, IN-J9Z39 and INMLA84 were also present. These metabolites are at significant levels in feedstuff commodities 

only.

Livestock metabolism studies were conducted on laying hens and lactating ruminants. For hens, 

most of the dose was excreted as unchanged parent compound (68-77% TRR). Residues in 

muscle, fat, and skin with fat were <0.01 ppm. Finite residues were found in eggs and liver.

Cyantraniliprole, IN-HGW87, IN-J9Z38, and IN-MLA84 were major residues in eggs. However, 

feeding studies conducted by dosing laying hens at levels of 3, 10 and 30 mg/kg for 28 days 

show significant levels of parent cyantraniliprole and metabolites IN-MYX98, IN-J9Z38, and/or

IN-MLA84 in eggs, muscle, liver and skin (with fat). For ruminants, cyantraniliprole was the 

major residue in milk, liver, kidney, muscle and fat. Also present in milk were 2 other major 

metabolites, IN-N7B69 and IN-MYX98. Feeding studies conducted with lactating cow at levels 

of 3, 10, 30 and 100 mg/kg for 28 days show significant levels of parent cyantraniliprole, and 

metabolites IN-N7B69, IN-J9Z38, IN-MLA84 and/or IN-MYX98 in cream, skim milk, muscle, 

liver, kidney and fat.
Page 4 of 7

Cyantraniliprole’s major routes of dissipation include alkaline-based hydrolysis (with DT50

values of 0.86 days at pH 9, 31 days at pH 7, and 222 days at pH 4), photodegradation in 

aqueous and moist soil environments (with DT50 values of 7.9 hours and 12.5 days, respectively), 

and aerobic and anaerobic biotransformation in terrestrial and aquatic environments (with DT50

values from 2.4 to 89 days). In terrestrial field studies, cyantraniliprole dissipated with DT50s 

ranging from 3.4 to 44 days. Cyantraniliprole appears not to volatilize and is characterized as 

being moderately mobile. Some degradates are more mobile than the parent and some are less 

mobile than the parent. Based on laboratory studies, the major (≥10% of the applied) 

environmental degradates of cyantraniliprole include IN-J9Z38 (hydrolysis and 

biotransformation in aerobic and anaerobic soil and aquatic systems), IN-NXX69 (aqueous 

phototransformation), IN-QKV54 (moist soil phototransformation), IN-RNU71 (moist soil 

phototransformation), IN-JSE76 (aerobic soil biotransformation), IN-JCZ38 (aerobic soil 

biotransformation), and IN-K5A78 (aerobic soil biotransformation). IN-J9Z38 formed under 

both microbial mediated and abiotic processes. Major degradates that continued to increase over 

time to study termination in various fate studies include IN-J9Z38, IN-RNU71, IN-JSE76, INJCZ38, and IN-K5A78. It should be noted that additional aerobic soil biotransformation studies 

were conducted with transformation products. Degradate half-lives ranged from 3.5 to 1800 

days, depending on transformation product and soil type. In addition, IN-K5A77, IN-K5A79, 

and IN-PLT97 were also detected in terrestrial field dissipation studies.

Post-meeting Note: Regarding TP (IN-NXX69), it is the opinion of the Canadian reviewer that it 

may be relevant for surface water modeling (although it is formed at pH 4 and perhaps pH 7 is 

more “environmentally relevant” but not for groundwater modeling since it is not a relevant 

pathway (not formed in soil).

Rationale

Parent cyantraniliprole was detected as a main residue in the metabolism studies, crop field trials 

and livestock feeding studies. Based on this, it is considered an appropriate marker for primary 

crops, rotational crops and livestock commodities and is recommended as the residue of concern 

(ROC) for tolerance enforcement. The following discussion is for the selection of the residue of 

concern for risk assessment purposes only. 

Primary Crops: Metabolism studies show parent cyantraniliprole as a major residue in rice, 

lettuce, cotton and tomato, and IN-J9Z38 as a major residue in rice and lettuce. The crop field 

trials show the presence of several metabolites at levels below the limit of quantitation or at 

significantly lower amounts than parent cyantraniliprole. The ROCKS recommends inclusion of 

parent only for risk assessment purposes.

Rotational Crops: Parent cyantraniliprole was the main residue in all the commodities for 

human consumption. Other metabolites were present at similar or lower levels than parent 

cyantraniliprole in feedstuff commodities only. Since the metabolites will not be significant 

contributors to the overall livestock dietary burden inclusion of the metabolites in the residue of 

concern will not significantly affect the dietary risk assessment. Therefore, the ROCKS 

recommends including only the parent cyantraniliprole as the residue of concern for rotational 

crops.
Page 5 of 7

Processed Commodities: Although degradates IN-J9Z38, IN-N5M09, and IN-F6L99 were 

formed under conditions of heat and/or hydrolysis, in general, only IN-J9Z38 was observed at

significant concentrations in a few processed commodities (e.g. cooked spinach, apple sauce). 

IN-N5M09 and IN-F6L99 were found at low levels in apple sauce and cooked spinach, but were 

absent (<LOQ) in a variety of other processed commodities. Based on this the ROCKS 

recommends parent cyantraniliprole and IN-J9Z38 as ROC.

Livestock: Feeding studies show that parent cyantraniliprole, IN-N7B69, IN-MLA84, INMYX98, and/or IN-J9Z38 are likely to be present in significant amount in some commodities. 

These metabolites are assumed to have similar toxicity to parent cyantraniliprole. The ROCKS 

recommends inclusion of parent cyantraniliprole for risk assessment purposes in all the 

commodities. In addition, inclusion of the metabolites that are significant levels in specific 

commodities (e.g. IN-N7B69, IN-MYX98 in milk; IN-MYX98 in muscle of poultry; IN-MLA84 

and IN-MYX98 in liver; IN-MLA84, IN-N7B69, and IN-MYX98 in kidney) is recommended 

and should be considered on a matrix-specific basis.

Water: Cyantraniliprole is likely to degrade extensively in the environment through several 

degradation routes to form IN-J9Z38, IN-NXX69, IN-QKV54, IN-RNU71, IN-JSE76, INJCZ38, IN-K5A78, IN-K5A77, IN-K5A79, and IN-PLT97. These degradates were either major 

degradates in relevant laboratory studies, formed in the field, or both. In the absence of toxicity 

data and similar analogs, these degradates are considered no more toxic than the parent 

compound and a total residue approach is recommended for risk assessment purposes. 

Therefore, the recommended ROC in water include cyantraniliprole, IN-J9Z38, IN-NXX69, INQKV54, IN-RNU71, IN-JSE76, IN-JCZ38, IN-K5A78, IN-K5A77, IN-K5A79, and IN-PLT97.

Recommended Tolerance Expression

The ROCKS recommends the following language for the tolerance expression for plant and 

livestock commodities:

Tolerances are established for residues of the insecticide cyantraniliprole, including its 

metabolites and degradates, in or on the commodities listed below. Compliance with 

the tolerance levels specified below is to be determined by measuring only 

cyantraniliprole (3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-

[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide), in or on the 

commodity. 
Page 6 of 7

Appendix 1. Cyantraniliprole and it major metabolites/degradates.

Common Name Chemical Name Structure

Cyantraniliprole

SYN545377

DPX-HGW86

CAS Name: 3-Bromo-1-(3-chloro-2-

pyridinyl)-N-[4-cyano-2-methyl-6 

[(methylamino)carbonyl]phenyl]-1H-pyrazole5-carboxamide

N

N

N

N

H

O

Cl

Br

HN O

N

IN-MLA84 CAS Name: 2-[3-Bromo-1-(3-chloro-2-

pyridinyl)-1H-pyrazol-5-yl]-1,4-dihydro-8-

methyl-4-oxo-6-quinazolinecarbonitrile N

NH

N

N

O

Br

N

Cl

CH3

N

IN-N7B69 CAS Name: 3-Bromo-1-(3-chloro-2-

pyridinyl)-N-[4-cyano-2-(hydroxymethyl)-6-

[(methylamino)carbonyl]phenyl]-1H-pyrazole5-carbonitrile

Br

Cl

O

O

NH

N

N

HN

N

N

CH3

HO

IN-MYX98 CAS Name: 3-Bromo-1-(3-chloro-2-

pyridinyl)-N-[4-cyano-2-[[(hydroxymethyl) 

amino]carbonyl]-6-[(methylphenyl]-1Hpyrazole-5-carboxamide

Br

Cl

O

O

NH

N

N

NH

N

N

CH3

HO

IN-J9Z38 CAS Name: 2-[3-Bromo-1-(3-chloro-2-

pyridinyl)-1H-pyrazol-5-yl]-3,4-dihydro-3,8-

dimethyl-4-oxo-6-quinazolinecarbonitrile

N

N

O

N

N

N

Br

Cl

N

IN-NXX69 CAS Name: 2-[[(4Z)-2-bromo-4Hpyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazin-4-

ylidene]amino]-5-cyano-N,3-

dimethylbenzamide

IN-QKV54 CAS Name: 2-(3-Bromo-1H-pyrazol-5-yl)-1,4-

dihydro-3,8-dimethyl-4-oxo-6-

quinazolinecarbonitrile

N

N

N

N

O

Br

HN O

N

N

N

O

N N

H

Br

N
Page 7 of 7

Appendix 1. Cyantraniliprole and it major metabolites/degradates.

Common Name Chemical Name Structure

IN-RNU71 CAS Name: 2-(2-Bromo-4-oxopyrazolo[1,5-

a]pyrido[3,2-e]pyrazin-5(4H)-yl)-5-cyano-N,3-

dimethylbenzamide

IN-JSE76 CAS Name: 4-[[[3-Bromo-1-(3-chloro-2-

pyridinyl)-1H-pyrazol-5-yl]carbonyl]amino]-3-

methyl-5-[(methylamino)carbonyl]benzoic 

acid

IN-JCZ38 CAS Name: 4-[[[3-Bromo-1-(3-chloro-2-

pyridinyl)-1H-pyrazol-5-yl]carbonyl]amino]-

N'3',5-dimethyl-1,3-benzenedicarboxamide

IN-K5A78 CAS Name: 2-[3-Bromo-1-(3-chloro-2-

pyridinyl)-1H-pyrazol-5-yl]-3,4-dihydro-3,8-

dimethyl-4-oxo-6-quinazolinecarboxylic acid

OH

O

N

N

O

N

N

N

Br

Cl

IN-K5A77 CAS Name: 2-[3-Bromo-1-(3-chloro-2-

pyridinyl)-1H-pyrazol-5-yl]-3,4-dihydro-3,8-

dimethyl-4-oxo-6-quinazolinecarboxamide

IN-K5A79 CAS Name: 3-(Aminocarbonyl)-4-[[[3-

bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-

yl]carbonyl]amino]-5-methylbenzoic acid

IN-PLT97 CAS Name: 2-[3-Bromo-1-(3-chloro-2-

pyridinyl)-1H-pyrazol-5-yl]-1,4-dihydro-8-

methyl-4-oxo-6-quinazolinecarboxylic acid

O

HN

N

N

N N

O Br

N

N

H

O

O

N

N

N

Cl

Br

O

OH

HN

O

NH2

HN O

N

H

O

N

N

N

Cl

Br

H2N

O

N

N

O

N

N

N

Br

Cl

N

H

H2N O

O

N

N

N

Cl

Br

O

HO

HO

O N

N

H

N

N

O

N

Br

Cl