Document ID: EPA-HQ-OPP-2008-0866-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-04-13T04:00Z

Notice of Filing of Pesticide Petition 8E7470 by Interregional Research
Project Number 4 (IR-4)

EPA Registration Division contact: Susan Stanton; (703) 305-5218

PP#: 8E7470

	EPA has received a pesticide petition (PP 8E7470) from the IR-4 Project
Headquarters, 500 College Road East, Suite 201 W, Princeton, NJ 08540
proposing, pursuant to section 408(d) of the Federal Food, Drug, and
Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.414 by
establishing a tolerance for residues of cyromazine,
(N-cyclopropyl-1,3,5-triazine-2,4,6-triamine) in or on the raw
agricultural commodity bean, succulent at 2.0 ppm.  EPA has determined
that the petition contains data or information regarding the elements
set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully
evaluated the sufficiency of the submitted data at this time or whether
the data support granting of the petition. Additional data may be needed
before EPA rules on the petition.

A. Residue Chemistry

	1. Plant metabolism. The metabolism of cyromazine in plants is
adequately understood for the purposes of these tolerances.

	2. Analytical method. Methods AG-408 and AG-417 as listed in the Food
and Drug Administration's Pesticide Analytical Manual (PAM), Vol-II are
adequate to enforce the proposed tolerances.

	3. Magnitude of residues. Residue field tests were conducted in typical
growing regions for succulent edible-podded beans and succulent shelled
beans. The data collected support the proposed tolerance of 2.0 ppm for
succulent beans. 

B. Toxicological Profile

	1. Acute toxicity. A rat acute oral toxicity study with a lethal dose
(LD50) of approximately 3,387 milligrams/kilogram (mg/kg) (toxicity
category III; moderately toxic). A rat acute dermal toxicity study with
a LD50 greater than 3,100 mg/kg (toxicity category III; moderately
toxic). A rat acute inhalation study with a lethal concentration (LC50)
greater than 2.9 mg/kg (toxicity category IV; slightly toxic). A primary
eye irritation study in the rabbit that showed no eye irritation. A
primary dermal irritation study in the rabbit that showed mild
irritation (toxicity category; IV). A dermal sensitization study in the
guinea pig that showed no sensitization.

	2. Genotoxicity. Studies on gene mutation and other genotoxic effects
showed no evidence of point mutation in an Ames test; no indication of
mutagenic effects in a dominant lethal test; and no evidence of
mutagenic effects in a nucleus anomaly test in Chinese hamsters.

	3. Reproductive and developmental toxicity. In a rat developmental
toxicity study, the maternal no observed adverse effect level (NOAEL)
was 100 mg/kg/day. The maternal lowest observed adverse effect level
(LOAEL) was 300 mg/kg based on decreased body weight gain and clinical
observations. The developmental NOAEL was 300 ppm. The developmental
LOAEL was 600 mg/kg based upon an increase of minor skeletal variation.

    In a rabbit developmental toxicity study, the maternal NOAEL was 10
mg/kg. The maternal LOAEL was 30 mg/kg based upon decreased body weight
gain and food consumption. The developmental NOAEL/LOAEL was greater
than or equal to 60 mg/kg.

    In a multi-generation study in rats, the systemic NOAEL was 30 ppm
(1.5 mg/kg). The systemic LOAEL was 1,000 ppm (50 mg/kg) based upon
decreased body weights associated with decreased food consumption. The
developmental/offspring systemic NOAEL was 1,000 ppm. The
developmental/offspring systemic LOAEL was 3,000 ppm (150 mg/kg) based
upon decreased body weight at birth through weaning. There were no
effects on reproductive parameters at the highest dose tested (HDT)
(3,000 ppm).

	4. Subchronic toxicity. In a 6-month feeding study in dogs, the NOAEL
was 30 ppm (0.75 mg/kg). The LOAEL was 300 ppm (7.5 mg/kg) based upon
decreased hematocrit and decreased hemoglobin. Groups of male and female
beagle dogs (4/sex/dose) were fed diets containing cyromazine at 0, 30,
300, or 3,000 ppm (0, 0.75, 7.5, or 75 mg/kg/day, respectively) for
6-months. No treatment-related effects were observed in survival,
clinical signs or body weight parameters. Pronounced effects on
hematologic parameters were manifested as decreases in hematocrit and
hemoglobin levels at 300 and 3,000 ppm.

	5. Chronic toxicity. In a 24-month feeding study in rats the NOAEL for
the study was 30 ppm (1.5 mg/kg/day). The LOAEL was 300 ppm (15.0 mg/kg)
based on decreased body weight. In a 24-month mouse chronic feeding
carcinogenicity study the NOAEL was 50 ppm (7.5 mg/kg/day). The LOAEL
was 1,000 ppm (150.0 mg/kg) based upon decreased body weight. There was
no evidence of carcinogenicity at 3,000 ppm (450 mg/kg). In a 24-month
rat chronic feeding carcinogenicity study the NOAEL was greater than
3,000 ppm (150 mg/kg) (HDT). There was no evidence of carcinogenicity at
3,000 ppm.

    Cancer Peer Review Committee determined that there is no evidence of
carcinogenicity in studies in either the mouse or rat. Based upon this
determination it can be concluded that cyromazine does not pose a cancer
risk.

	6. Animal metabolism. The metabolism of cyromazine has been adequately
characterized in the rat, goat, and chicken.

	7. Metabolite toxicology. EPA has removed melamine, a metabolite of
cyromazine, from the tolerance expression as a residue of toxicological
concern. For more information on melamine, see the Federal Register of
September 15, 1999 (64 FR 50043) (FRL-6098-7).

	8. Endocrine disruption. Cyromazine does not belong to a class of
chemicals proven to have adverse effects on the endocrine system. There
is no evidence that cyromazine has any effect on endocrine function in
developmental or reproduction studies.

C. Aggregate Exposure

	1. Dietary exposure. A chronic (Tier I) dietary exposure evaluation was
made for cyromazine using the Dietary Exposure Evaluation Model
(DEEM-FCIDTM, version 2.03) from Exponent. All consumption data for
these assessments was taken from the USDA’s Continuing Survey of Food
Intake by individuals (CSFII) with the 1994-96 consumption database and
the Supplemental CSFII children’s survey (1998) consumption database.
The chronic exposure assessment was based on current and proposed
tolerances for cyromazine and the percent of crop treated was assumed to
be 100% for all commodities. Current cyromazine tolerances on food crops
include dry beans (except cowpeas), lima beans, broccoli, Abyssinian
cabbage, seakale cabbage, bulb garlic, great-headed bulb garlic, Hanover
salad leaves, leafy vegetables (Crop Group 4 except brassica), leeks,
mangoes (import), mushrooms, bulb onions, green onions, potato onions,
tree onions, welsh onions, peppers, potatoes, bulb rakkyo, bulb shallot,
fresh shallot (leaves), tomatoes, turnip greens, Brassica vegetables
(Crop Group 5 except broccoli), and cucurbit vegetables (Crop Group 9).
Tolerances for indirect or inadvertent residues of cyromazine include
cottonseed (undelinted), sweet corn kernels plus cob with husks removed,
sweet corn forage, sweet corn stover, radish roots, and radish tops
(leaves). Current cyromazine tolerances in animal commodities include
fat, kidney, meat, and meat byproducts of cattle, goats, hogs, horses,
and sheep, plus fat, meat, and meat byproducts of poultry (chicken layer
hens and chicken breeder hens only). Drinking water estimates were
incorporated directly into the dietary exposure assessment using the
higher of the estimated drinking water concentrations (EDWCs) for
surface and ground water.

	i. Food. Chronic Exposure. The Tier I cyromazine chronic dietary risk
assessment was performed for all population subgroups with a chronic
reference dose of 0.075 mg/kg/day based on a chronic oral toxicity
study in dogs with a no observable adverse effect level (NOAEL) of 7.5
mg/kg/day and an uncertainty factor of 100X for intra- and inter-species
variations. For the purpose of aggregate risk assessment, the exposure
values were expressed in terms of margin of exposure (MOE), which was
calculated by dividing the NOAEL by the exposure for each population
subgroup. In addition, exposure was expressed as a percent of the
reference dose (%RfD). Chronic dietary (food only) exposure to the U.S.
population resulted in a MOE of 1,082 (9.2% of the chronic RfD of 0.075
mg/kg/day). The most exposed sub-population was children (1-2 years old)
with a MOE of 617 (16.2% of the chronic RfD of 0.075 mg/kg/day). Since
the benchmark MOE for this assessment is 100 and since the EPA generally
has no concern for exposures below 100% of the RfD, Syngenta believes
that there is a reasonable certainty that no harm will result from
dietary (food only) exposure to residues arising from all current and
proposed uses of cyromazine. 

Cancer. Cyromazine is classified as a Group E carcinogen (evidence of
non-carcinogenicity for humans) and was shown not to be carcinogenic in
mice or rats following long-term dietary administration.

(15.5 ppb) for surface water was input into the DEEM-FCID™ software as
water, direct and indirect, all sources to obtain the chronic dietary
exposure from water. Chronic drinking water exposure to the U.S.
Population resulted in a MOE of 22,957 (0.4% of the chronic RfD of 0.075
mg/kg/day). The most exposed sub-population was all infants (<1 year
old) with a MOE of 7,002 (1.4% of the chronic RfD of 0.075 mg/kg/day).
Since the benchmark MOE for this assessment is 100 and since the EPA
generally has no concern for exposures below 100% of the RfD, Syngenta
believes that there is a reasonable certainty that no harm will result
from chronic drinking water exposure to residues arising from all
current and proposed uses of cyromazine.

	2. Non-dietary exposure. Cyromazine is currently registered for
commercial outdoor use on landscape ornamentals and commercial
interiorscapes. There are no lawn uses or indoor residential uses and
significant residential exposure is not expected.

D. Cumulative Effects

	Cumulative Exposure to Substances with a Common Mechanism of Toxicity.
Section 408(b)(2)(D)(v) 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.” Neither Syngenta nor EPA has, at this
time, available data to determine whether cyromazine has a common
mechanism of toxicity with other substances or the methodology to
include this pesticide in a cumulative risk assessment. Cyromazine does
not appear to produce a toxic metabolite produced by other substances.

E. Safety Determination

	1. U.S. population. The chronic dietary exposure analysis (food plus
water) showed that exposure from all current and proposed cyromazine
residues in or on food crops would result in a MOE of 1,033 (9.7% of the
chronic RfD of 0.075 mg/kg/day) for the general U.S. population. Since
the aggregate MOE of 1,033 exceeds the benchmark MOE of 100, Syngenta
believes that there is a reasonable certainty that no harm will result
from aggregate exposure to residues arising from all current and
proposed cyromazine uses, including anticipated dietary exposure from
food, water, and all other types of non-occupational exposures.

	2. Infants and children. The chronic dietary exposure analysis (food
plus water) showed that exposure from all current and proposed
cyromazine residues in or on food crops would result in a MOE of 593
(16.9% of the chronic RfD of 0.075 mg/kg/day) for the most sensitive
population subgroup, children, 1-2 years old. Since the worst-case
aggregate MOE of 593 exceeds the benchmark MOE of 100, Syngenta believes
that there is a reasonable certainty that no harm will result from
aggregate exposure to residues arising from all current and proposed
cyromazine uses, including anticipated dietary exposure from food,
water, and all other types of non-occupational exposures.

F. International Tolerances

	The U.S. tolerances and Codex Maximum Residue Levels (MRLs) are
compatible for ruminant tissue, poultry tissue, peppers, and tomatoes.
Codex MRLs and U.S. tolerances are incompatible for milk, eggs, celery,
cucumber, lettuce, melons, and mushrooms.