[Federal Register Volume 78, Number 120 (Friday, June 21, 2013)]
[Rules and Regulations]
[Pages 37468-37474]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2013-14914]



40 CFR Part 180

[EPA-HQ-OPP-2012-0177; FRL-9387-3]

Cyproconazole; Pesticide Tolerances

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.


SUMMARY: This regulation establishes tolerances for residues of 
cyproconazole in or on peanut and peanut, hay. Syngenta Crop 
Protection, LLC. requested these tolerances under the Federal Food, 
Drug, and Cosmetic Act (FFDCA).

DATES: This regulation is effective June 21, 2013. Objections and 
requests for hearings must be received on or before August 20, 2013, 
and must be filed in accordance with the instructions provided in 40 
CFR part 178 (see also Unit I.C. of the SUPPLEMENTARY INFORMATION).

ADDRESSES: The docket for this action, identified by docket 
identification (ID) number EPA-HQ-OPP-2012-0177, is available at http://www.regulations.gov or at the Office of Pesticide Programs Regulatory 
Public Docket (OPP Docket) in the Environmental Protection Agency 
Docket Center (EPA/DC), EPA West Bldg., Rm. 3334, 1301 Constitution 
Ave. NW., Washington, DC 20460-0001. The Public Reading Room is open 
from 8:30 a.m. to 4:30 p.m., Monday through Friday, excluding legal 
holidays. The telephone number for the Public Reading Room is (202) 
566-1744, and the telephone number for the OPP Docket is (703) 305-
5805. Please review the visitor instructions and additional information 
about the docket available at http://www.epa.gov/dockets.

FOR FURTHER INFORMATION CONTACT: Shaunta Hill, Registration Division 
(7505P), Office of Pesticide Programs, Environmental Protection Agency, 
1200 Pennsylvania Ave. NW., Washington, DC 20460-0001; telephone 
number: (703) 347-8961; email address: [email protected].


I. General Information

A. Does this action apply to me?

    You may be potentially affected by this action if you are an 
agricultural producer, food manufacturer, or pesticide manufacturer. 
The following list of North American Industrial Classification System 
(NAICS) codes is not intended to be exhaustive, but rather provides a 
guide to help readers determine whether this document applies to them. 
Potentially affected entities may include:
     Crop production (NAICS code 111).
     Animal production (NAICS code 112).
     Food manufacturing (NAICS code 311).
     Pesticide manufacturing (NAICS code 32532).

B. How can I get electronic access to other related information?

    You may access a frequently updated electronic version of EPA's 
tolerance regulations at 40 CFR part 180 through the Government 
Printing Office's eCFR site at http://www.ecfr.gov/cgi-bin/text-idx?&c=ecfr&tpl=/ecfrbrowse/Title40/40tab_02.tpl. To access the OCSPP 
test guidelines referenced in this document electronically, please go 
to http://www.epa.gov/ocspp and select ``Test Methods and Guidelines.''

C. How can I file an objection or hearing request?

    Under FFDCA section 408(g), 21 U.S.C. 346a, any person may file an 
objection to any aspect of this regulation and may also request a 
hearing on those objections. You must file your objection or request a 
hearing on this regulation in accordance with the instructions provided 
in 40 CFR part 178. To ensure proper receipt by EPA, you must identify 
docket ID number EPA-HQ-OPP-2012-0177 in the subject line on the first 
page of your submission. All objections and requests for a hearing must 
be in writing, and must be received by the Hearing Clerk on or before 
August 20, 2013. Addresses for mail and hand delivery of objections and 
hearing requests are provided in 40 CFR 178.25(b).
    In addition to filing an objection or hearing request with the 
Hearing Clerk as described in 40 CFR part 178, please submit a copy of 
the filing (excluding any Confidential Business Information (CBI)) for 
inclusion in the public docket. Information not marked confidential 
pursuant to 40 CFR part 2 may be disclosed publicly by EPA without 
prior notice. Submit the non-CBI copy of your objection or hearing 
request, identified by docket ID number EPA-HQ-OPP-2012-0177, by one of 
the following methods:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the online instructions for submitting comments. Do not submit 
electronically any information you consider to be CBI or other 
information whose disclosure is restricted by statute.
     Mail: OPP Docket, Environmental Protection Agency Docket 
Center (EPA/DC), (28221T), 1200 Pennsylvania Ave. NW., Washington, DC 
     Hand Delivery: To make special arrangements for hand 
delivery or delivery of boxed information, please follow the 
instructions at http://www.epa.gov/dockets/contacts.htm.

Additional instructions on commenting or visiting the docket, along 
with more information about dockets generally, is available at http://www.epa.gov/dockets.

II. Summary of Petitioned-for Tolerance

    In the Federal Register of May 23, 2012 (77 FR 30481) (FRL-9347-8), 
EPA issued a document pursuant to FFDCA section 408(d)(3), 21 U.S.C. 
346a(d)(3), announcing the filing of a pesticide petition (PP 1F7956) 
by Syngenta Crop Protection, LLC., P.O. Box 18300, Greensboro, NC 
24719. The petition requested that 40 CFR 180.485 be amended by 
establishing tolerances for residues of the fungicide cyproconazole, in 
or on peanut, hay at 6.0 parts per million (ppm), and peanut, nutmeat; 
peanut, meal; peanut, butter; and peanut, refined oil at 0.03 ppm. That 
document referenced a summary of the petition prepared by Syngenta Crop 
Protection, the registrant, which is available in the docket, http://www.regulations.gov. There were no substantive comments received in 
response to the notice of filing.
    Based upon review of the data supporting the petition, EPA has 
modified the requested tolerance levels and crops for which tolerances 
were needed. The reasons for these changes are explained in Unit IV.C.

III. Aggregate Risk Assessment and Determination of Safety

    Section 408(b)(2)(A)(i) of FFDCA allows EPA to establish a 
tolerance (the legal limit for a pesticide chemical residue in or on a 
food) only if EPA determines that the tolerance is ``safe.'' Section 
408(b)(2)(A)(ii) of FFDCA defines ``safe'' to mean that ``there is a 
reasonable certainty that no harm will result from aggregate exposure 
to the pesticide chemical residue, including all anticipated dietary 
exposures and all other exposures for which there is reliable 
information.'' This includes exposure through drinking water and in 
residential settings, but does not include occupational exposure. 
Section 408(b)(2)(C) of FFDCA requires EPA to give special 
consideration to exposure of infants and children to the pesticide 
chemical residue in establishing a

[[Page 37469]]

tolerance and to ``ensure that there is a reasonable certainty that no 
harm will result to infants and children from aggregate exposure to the 
pesticide chemical residue. . . .''
    Consistent with FFDCA section 408(b)(2)(D), and the factors 
specified in FFDCA section 408(b)(2)(D), EPA has reviewed the available 
scientific data and other relevant information in support of this 
action. EPA has sufficient data to assess the hazards of and to make a 
determination on aggregate exposure for cyproconazole including 
exposure resulting from the tolerances established by this action. 
EPA's assessment of exposures and risks associated with cyproconazole 

A. Toxicological Profile

    EPA has evaluated the available toxicity data and considered its 
validity, completeness, and reliability as well as the relationship of 
the results of the studies to human risk. EPA has also considered 
available information concerning the variability of the sensitivities 
of major identifiable subgroups of consumers, including infants and 
    The acute studies demonstrate that cyproconazole is moderately 
toxic by the oral, dermal, and inhalation routes. It is neither an eye 
nor dermal irritant. Cyproconazole did not cause dermal sensitization. 
Consistent with similar anti-fungal pesticide active ingredients in 
this class (e.g., tetraconazole), the critical toxicological effects 
for cyproconazole in mammals appear to be indicative of hepatotoxicity. 
These effects include elevated levels of the liver enzymes lactate 
dehydrogenase (LDH) and aspartate aminotransferase, increased liver 
weight (relative and absolute), vacuolization, fatty changes, 
hepatocytomegaly, hypertrophy, and single-cell necrosis. For both 
subchronic and chronic durations, hepatotoxicity was observed in rats, 
mice and dogs, and all of these species appeared to be equally 
sensitive to cyproconazole toxicity with regards to the range of the 
doses tested (~0.5 to 130 milligrams/kilogram/day (mg/kg/day)). Other 
notable effects seen in rat subchronic oral feeding studies included 
increased macrophages in the lung, increased white blood cell counts 
and globulins, decreased spleen weights, histocytosis of the spleen, 
and spleen micropathology.
    There are two dermal toxicity studies submitted for cyproconazole, 
both showing effects similar to the oral studies. In the 21-day study, 
dermal exposure to cyproconazole resulted in decreased body-weight gain 
and food consumption (males), increased aspartate aminotransferase 
(males), increased creatinine (females), and increased cholesterol in 
both sexes at the highest dose tested (1,250 mg/kg/day). In the 28-day 
study, toxicity occurred at the mid-dose (100 mg/kg/day). These effects 
included increased plasma globulin, protein and cholesterol, and 
hemosiderin deposition in the spleen in females (1,000 mg/kg/day in 
males), hypertrophy of the thyroid follicular epithelium in both males 
and females, and increased incidences of centrilobular hepatocellular 
hypertrophy in males (1,000 mg/kg/day in females).
    The developmental studies indicate that cyproconazole causes 
developmental toxicity. There are two developmental toxicity studies in 
rabbits, which were more sensitive for developmental effects than the 
rat. In the older study using chinchilla rabbits, the pups showed 
increased susceptibility with toxicity occurring at the lowest dose 
tested (2 mg/kg/day, the developmental no observed adverse effect level 
(NOAEL) was not established). These effects included increased 
incidences of hydrocephalus internus (abnormal accumulation of cerebral 
spinal fluid in the ventricles of the brain). The maternal lowest 
observed adverse effect level (LOAEL) was 10 mg/kg/day. This 
developmental toxicity study was classified unacceptable and does not 
satisfy the guideline requirement for a developmental toxicity study 
(OPPTS Guideline 870.3700; OECD 414) in the rabbit because the 
concentrations of test material were not within the acceptable range 
(15% of nominal concentration) for the mid- and high-dose 
suspensions immediately after preparation. In the most recent study 
using New Zealand white rabbits, cyproconazole produced increased 
incidences of malformed fetuses and litters with malformed fetuses 
(hydrocephalus and kidney agenesis) at doses lower than the doses that 
produced maternal toxicity (50 mg/kg/day for dams and 10 mg/kg/day for 
fetuses). In rats, cyproconazole increased the incidences of 
supernumerary ribs at the same doses at which maternal adverse effects 
(decreased body-weight gain) were observed (12 mg/kg/day). There was no 
evidence of reproductive toxicity in the 2-generation reproduction 
toxicity study. The parental toxicity in the 2-generation reproduction 
study was manifested as increased lipid storage and relative liver 
weights in males and increased relative liver weights in females (8.29 
mg/kg/day). No offspring toxicity was observed at any of the doses 
    Although there was evidence of carcinogenicity found in a mouse 
study, EPA has determined that cyproconazole is ``not likely to be 
carcinogenic to humans'' at doses that do not cause a mitogenic 
response in the liver (Ref. 1). In contrast to rodent cells, there are 
some limited data to suggest that constitutive androstane receptor 
(CAR) activation does not stimulate cell proliferation or inhibit 
apoptosis in human cells. However, the literature does not yet support 
the conclusion that CAR activation is not biologically plausible in 
humans. This conclusion is based on the weight of evidence that 
supports a non-genotoxic mitogenic mode of action for cyproconazole. 
The activation of the CAR receptor, the required initiating event, 
leads to a cascade of key events resulting in liver tumor development 
in mice. The data did not support: (1) Peroxisome proliferation, (2) 
mutagenesis, or (3) cytotoxicity followed by sustained regenerative 
proliferation as alternative modes of action. The quantification of 
carcinogenic potential is not required. The current reference dose 
(RfD) of 0.01 mg/kg/day is based on a 1-year dog study in which 
hepatotoxicity and organ weight changes were seen at 3.2 mg/kg/day and 
no adverse effects were observed at 1 mg/kg/day (NOAEL). This RfD would 
be protective of any liver effects caused by cyproconazole in the mouse 
toxicity studies or mode of action studies at higher doses.
    There is no evidence of targeted neurotoxicity in the toxicity 
database. There were no central nervous system (CNS) malformations 
present in the developmental toxicity studies in rats and rabbits. In a 
2-generation reproduction study in rats, there were no findings in pups 
that were suggestive of changes in neurological development. 
Additionally, there was no evidence of neurotoxicity in other studies.
    Finally, there is no evidence that cyproconazole is an 
immunotoxicant. Although there is no immunotoxicity study currently 
available for cyproconazole, the available data indicate that 
cyproconazole does not have immunotoxic effects. This is consistent 
with the fact that the target organ is the liver, which is similar to 
the other triazole fungicides, which do not have immunotoxic effects.
    Specific information on the studies received and the nature of the 
adverse effects caused by cyproconazole as well as the NOAEL and the 
LOAEL from the toxicity studies can be found at http://www.regulations.gov in document ``Cyproconazole. Tolerance Petition for

[[Page 37470]]

Residues in/on Peanuts, Human-Health Risk Assessment'' in docket ID 
number EPA-HQ-OPP-2012-0177.

B. Toxicological Points of Departure/Levels of Concern

    Once a pesticide's toxicological profile is determined, EPA 
identifies toxicological points of departure (POD) and levels of 
concern to use in evaluating the risk posed by human exposure to the 
pesticide. For hazards that have a threshold below which there is no 
appreciable risk, the toxicological POD is used as the basis for 
derivation of reference values for risk assessment. PODs are developed 
based on a careful analysis of the doses in each toxicological study to 
determine the dose at which no adverse effects are observed (the NOAEL) 
and the lowest dose at which adverse effects of concern are identified 
(the LOAEL). Uncertainty/safety factors are used in conjunction with 
the POD to calculate a safe exposure level--generally referred to as a 
population-adjusted dose (PAD) or a reference dose (RfD)--and a safe 
margin of exposure (MOE). For non-threshold risks, the Agency assumes 
that any amount of exposure will lead to some degree of risk. Thus, the 
Agency estimates risk in terms of the probability of an occurrence of 
the adverse effect expected in a lifetime. For more information on the 
general principles EPA uses in risk characterization and a complete 
description of the risk assessment process, see http://www.epa.gov/pesticides/factsheets/riskassess.htm.

A summary of the toxicological endpoints for cyproconazole used for 
human risk assessment is shown in Table 1 of this unit.

 Table 1--Summary of Toxicological Doses and Endpoints for Cyproconazole for Use in Human Health Risk Assessment
                                                     Uncertainty/FQPA  RfD, PAD, LOC for         Study and
       Exposure scenario                POD                 SF          risk assessment    toxicological effects
Acute Dietary (General           N/A..............  N/A..............  N/A..............  A dose and endpoint
 population, including infants                                                             attributable to a
 and children).                                                                            single dose were not
                                                                                           identified in the
                                                                                           database including
                                                                                           the developmental
                                                                                           toxicity studies.
Acute Dietary (Females 13-49     NOAEL = 2 mg/kg/   UFA = 10X........  aPAD = aRfD =      Prenatal Developmental
 years of age).                   day.              UFH = 10X........   0.02 mg/kg/day.    toxicity Study--New
                                                    FQPA SF = 1X.....                      Zealand white rabbits
                                                                                          Developmental LOAEL =
                                                                                           10 mg/kg/day based on
                                                                                           increased incidence
                                                                                           of malformed fetuses
                                                                                           and litters with
                                                                                           malformed fetuses.
Chronic Dietary (All             NOAEL = 1.0 mg/kg/ UFA = 10X........  cPAD = cRfD =      Chronic oral toxicity
 populations).                    day.              UFH = 10X........   0.01 mg/kg/day.    study--dog
                                                    FQPA SF = 1X.....                     LOAEL = 3.2 mg/kg/day
                                                                                           based on liver
                                                                                           effects (P450
                                                                                           induction in females
                                                                                           and histopathology,
                                                                                           laminar eosinophilic
                                                                                           bodies in males).
Short (1-30 days)- and           NOAEL = 10 mg/kg/  UFA = 10X........  Residential LOC    28-Day Dermal Study--
 Intermediate (1-6 months)-Term   day.              UFH = 10X........   for MOE = 100.     rat
 Dermal.                                            FQPA SF = 1X.....                     LOAEL = 100 mg/kg/day,
                                                                                           based on increased
                                                                                           plasma globulin,
                                                                                           protein and
                                                                                           cholesterol, and
                                                                                           deposition in the
                                                                                           spleen in females,
                                                                                           and hypertrophy of
                                                                                           the thyroid
                                                                                           follicular epithelium
                                                                                           in both males and
Cancer (oral, dermal,                 EPA has classified cyproconazole as ``not likely to be carcinogenic to
 inhalation).                      humans'', according to EPA Proposed Guidelines for Carcinogen Risk Assessment
                                                                 (April 10, 1996).
FQPA SF = Food Quality Protection Act Safety Factor. LOAEL = lowest-observed-adverse-effect-level. LOC = level
  of concern. mg/kg/day = milligrams/kilogram/day. MOE = margin of exposure. NOAEL = no-observed-adverse-effect-
  level. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. UF = uncertainty factor.
  UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among
  members of the human population (intraspecies).

C. Exposure Assessment

    1. Dietary exposure from food and feed uses. In evaluating dietary 
exposure to cyproconazole, EPA considered exposure under the 
petitioned-for tolerances as well as all existing cyproconazole 
tolerances in 40 CFR 180.485. EPA assessed dietary exposures from 
cyproconazole in food as follows:
    i. Acute exposure. Quantitative acute dietary exposure and risk 
assessments are performed for a food-use pesticide, if a toxicological 
study has indicated the possibility of an effect of concern occurring 
as a result of a 1-day or single exposure. In conducting the acute 
dietary exposure assessment, EPA used the food consumption data from 
the U.S. Department of Agriculture's (USDA) National Health and 
Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). 
This dietary survey was conducted from 2003 to 2008. As to residue 
levels in food, an unrefined acute dietary exposure and risk analysis 
was performed assuming tolerance-level residues, 100% crop treated, 
DEEM (ver. 7.81) default processing factors.
    ii. Chronic exposure. In conducting the chronic dietary exposure 
assessment, EPA used the food consumption data from the USDA's NHANES/
WWEIA. This dietary survey was conducted from 2003 to 2008. An 
unrefined chronic dietary exposure and risk analysis was performed 
assuming tolerance-level residues, 100% crop treated, DEEM (ver. 7.81) 
default processing factors.
    iii. Cancer. Based on the data summarized in Unit III.A., EPA has 
concluded that cyproconazole does not pose a cancer risk to humans. 
Therefore, a dietary exposure assessment for the purpose of assessing 
cancer risk is unnecessary.
    iv. Anticipated residue and percent crop treated (PCT) information. 
EPA did not use anticipated residue and/or PCT information in the 
dietary assessment for cyproconazole. Tolerance-level

[[Page 37471]]

residues and 100% crop treated was assumed for all food commodities.
    2. Dietary exposure from drinking water. The Agency used screening-
level water exposure models in the dietary exposure analysis and risk 
assessment for cyproconazole in drinking water. These simulation models 
take into account data on the physical, chemical, and fate/transport 
characteristics of cyproconazole. Further information regarding EPA 
drinking water models used in pesticide exposure assessment can be 
found at http://www.epa.gov/oppefed1/models/water/index.htm.
    Based on the First Index Reservoir Screening Tool (FIRST) and 
Screening Concentration in Ground Water (SCI-GROW) models, the 
estimated drinking water concentrations (EDWCs) of cyproconazole for 
acute exposures are estimated to be 113 parts per billion (ppb) for 
surface water and 1.52 ppb for ground water. For chronic exposures for 
non-cancer assessments are estimated to be 43 ppb for surface water and 
1.52 ppb for ground water.
    Modeled estimates of drinking water concentrations were directly 
entered into the dietary exposure model. Since the EDWC estimates from 
surface water were higher than those from ground water, EDWC estimates 
in surface water were used in both acute and chronic dietary risk 
    3. From non-dietary exposure. The term ``residential exposure'' is 
used in this document to refer to non-occupational, non-dietary 
exposure (e.g., for lawn and garden pest control, indoor pest control, 
termiticides, and flea and tick control on pets).
    Cyproconazole is not registered for any specific use patterns that 
would result in residential handler exposure. Cyproconazole is proposed 
for use on golf course turf, which may result in post-application 
dermal exposure to golfers (both adults and children). No chemical-
specific data were available to assess potential short-term dermal 
post-application exposures to adult and youth golfers. Therefore, a 
series of assumptions and exposure factors served as the basis for 
completing the residential post-application risk assessment. Each 
assumption and factor is detailed in the 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential-exposure-sop.html). Post-
application oral and inhalation exposures, as well as residential 
handler exposures, are not expected based on the current use patterns 
for cyproconazole. Further information regarding EPA standard 
assumptions and generic inputs for residential exposures may be found 
at http://www.epa.gov/pesticides/trac/science/trac6a05.pdf.
    4. Cumulative effects from substances with a common mechanism of 
toxicity. 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.''
    Cyproconazole is a member of the triazole-containing class of 
pesticides. Although conazoles act similarly in plants by inhibiting 
ergosterol biosynthesis, there is not necessarily a relationship 
between their pesticidal activity and their mechanism of toxicity in 
mammals. Structural similarities do not constitute a common mechanism 
of toxicity. Evidence is needed to establish that the chemicals operate 
by the same, or essentially the same, sequence of major biochemical 
events (Ref. 2). In conazoles, however, a variable pattern of 
toxicological responses is found; some are hepatotoxic and 
hepatocarcinogenic in mice. Some induce thyroid tumors in rats. Some 
induce developmental, reproductive, and neurological effects in 
rodents. Furthermore, the conazoles produce a diverse range of 
biochemical events including altered cholesterol levels, stress 
responses, and altered DNA methylation. It is not clearly understood 
whether these biochemical events are directly connected to their 
toxicological outcomes. Thus, there is currently no evidence to 
indicate that conazoles share common mechanisms of toxicity and EPA is 
not following a cumulative risk approach based on a common mechanism of 
toxicity for the conazoles. For information regarding EPA's procedures 
for cumulating effects from substances found to have a common mechanism 
of toxicity, see EPA's Web site at http://www.epa.gov/pesticides/cumulative.
    Cyproconazole is a triazole-derived pesticide. This class of 
compounds can form the common metabolite 1,2,4-triazole and two 
triazole conjugates (triazolylalanine and triazolylacetic acid). To 
support existing tolerances and to establish new tolerances for 
triazole-derivative pesticides, including cyproconazole, EPA conducted 
a human health risk assessment for exposure to 1,2,4-triazole, 
triazolylalanine, and triazolylacetic acid resulting from the use of 
all current and pending uses of any triazole-derived fungicide. The 
risk assessment is a highly conservative, screening-level evaluation in 
terms of hazards associated with common metabolites (e.g., use of a 
maximum combination of uncertainty factors) and potential dietary and 
non-dietary exposures (i.e., high end estimates of both dietary and 
non-dietary exposures). In addition, the Agency retained the additional 
10X FQPA Safety Factor for the protection of infants and children. The 
assessment includes evaluations of risks for various subgroups, 
including those comprised of infants and children. The Agency's 
complete risk assessment is found in the propiconazole reregistration 
docket at http://www.regulations.gov, docket identification (ID) number 
    An updated dietary exposure and risk analysis for the common 
triazole metabolites 1,2,4-triazole (T), triazolylalanine (TA), 
triazolylacetic acid (TAA), and triazolylpyruvic acid (TP) was 
conducted and completed in August 2012, in association with a 
registration request for the triazole fungicide, propiconazole. Residue 
data demonstrated that there was no increase in exposure to the common 
triazole metabolites with the proposed use. The tolerances for 
cyproconazole in/on peanuts covered by this action are not expected to 
change the risk of exposure to the triazoles determined in that risk 
analysis. The document, titled ``Common Triazole Metabolites: Updated 
Aggregate Human Health Risk Assessment to Address the Amended 
Propiconazole Section 3 Registration to Add Use on Sugarcane'' may be 
found in docket ID number EPA-HQ-OPP-2012-0427.

D. Safety Factor for Infants and Children

    1. In general. Section 408(b)(2)(C) of FFDCA provides that EPA 
shall apply an additional tenfold (10X) margin of safety for infants 
and children in the case of threshold effects to account for prenatal 
and postnatal toxicity and the completeness of the database on toxicity 
and exposure unless EPA determines based on reliable data that a 
different margin of safety will be safe for infants and children. This 
additional margin of safety is commonly referred to as the FQPA Safety 
Factor (SF). In applying this provision, EPA either retains the default 
value of 10X, or uses a different additional safety factor when 
reliable data available to EPA support the choice of a different 
    2. Prenatal and postnatal sensitivity. There are no residual 
uncertainties with regard to prenatal and postnatal toxicity, and the 
database is complete for purposes of assessing prenatal and postnatal 
toxicity. There is evidence that cyproconazole is a developmental

[[Page 37472]]

toxicant; however, the LOC is low since: (1) The effects in fetuses are 
well-characterized with a clear NOAEL and (2) the developmental 
toxicity study where increased susceptibility was observed is being 
used for the acute dietary endpoint (females 13-49 years), which will 
be protective of effects in infants and children. There is no evidence 
of reproductive toxicity or neurotoxicity in the cyproconazole 
    3. Conclusion. EPA has determined that reliable data show the 
safety of infants and children would be adequately protected if the 
FQPA SF were reduced to 1X. That decision is based on the following 
    i. The toxicity database for cyproconazole is complete, except for 
an immunotoxicity study. As noted in Unit III.A., the concern for the 
lack of this study is low because there is no evidence that 
cyproconazole causes immunotoxic effects. EPA does not believe that an 
immunotoxicity study will result in a lower point of departure (POD) 
than that which is currently in use for overall risk assessment. As 
such, a database uncertainty factor is not necessary to account for the 
lack of an immunotoxicity study.
    ii. There is no indication that cyproconazole is a neurotoxic 
chemical and there is no need for a developmental neurotoxicity study 
or additional UFs to account for neurotoxicity.
    iii. While there is evidence that exposure to cyproconazole results 
in increased susceptibility in in utero rabbits, EPA does not believe 
that the FQPA safety factor of 10X is necessary to protect infants and 
children for the reasons stated in Unit III.D.2. above.
    iv. There are no residual uncertainties identified in the exposure 
databases. EPA made conservative (protective) assumptions in the ground 
water and surface water modeling used to assess exposure to 
cyproconazole in drinking water. These assessments will not 
underestimate the exposure and risks posed by cyproconazole.

E. Aggregate Risks and Determination of Safety

    EPA determines whether acute and chronic dietary pesticide 
exposures are safe by comparing aggregate exposure estimates to the 
acute PAD (aPAD) and chronic PAD (cPAD). For linear cancer risks, EPA 
calculates the lifetime probability of acquiring cancer given the 
estimated aggregate exposure. Short-, intermediate-, and chronic-term 
risks are evaluated by comparing the estimated aggregate food, water, 
and residential exposure to the appropriate PODs to ensure that an 
adequate MOE exists.
    1. Acute risk. Using the exposure assumptions discussed in this 
unit for acute exposure, the acute dietary exposure from food and water 
to cyproconazole will occupy 32% of the aPAD for females 13-49 years 
old. The acute dietary exposure and risk analysis was conducted only 
for females 13-49 years old since an endpoint of concern attributable 
to a single dose for the general population was not identified.
    2. Chronic risk. Using the exposure assumptions described in this 
unit for chronic exposure, EPA has concluded that chronic exposure to 
cyproconazole from food and water will utilize 28% of the cPAD for 
infants (<1 years old), the population group receiving the greatest 
exposure. There are no residential uses for cyproconazole.
    3. Short-term risk. Short-term aggregate exposure is calculated by 
aggregating short-term residential exposure plus chronic exposure to 
food and water (considered to be a background exposure level). A short-
term adverse effect was identified; however, cyproconazole is not 
currently registered for any use patterns that would result in short-
term residential exposure. In consideration of a pending turf use for 
cyproconazole, a short-term aggregate assessment was completed. The 
pending golf course use is the only use that may result in residential 
exposure. The golfer exposure (dermal) represents the highest 
residential exposure of all potential adult exposure scenarios. 
Therefore, the short-term assessment is protective of all potential 
exposures resulting from the pending golf course use. For the short-
term aggregate assessment, the short-term oral NOAEL of 1.5 mg/kg/day 
(from the 90-day oral rat study) is compared to the total (dietary + 
residential) exposure to calculate risk. Since the aggregate MOEs are 
greater than 100, the calculated risks do not exceed the Agency's LOCs.
    4. Intermediate-term risk. Intermediate-term aggregate exposure 
takes into account intermediate-term residential exposure plus chronic 
exposure to food and water (considered to be a background exposure 
level). There are no residential scenarios that result in intermediate-
term exposure; therefore, an intermediate-term aggregate exposure and 
risk assessment is not required.
    5. Aggregate cancer risk for U.S. population. Although there was 
evidence of carcinogenicity found in a mouse study, EPA has determined 
that cyproconazole is ``not likely to be carcinogenic to humans'' at 
doses that do not cause a mitogenic response in the liver (Ref. 1). As 
a result, an aggregate cancer exposure and risk assessment is not 
required, as cyproconazole is not expected to pose a cancer risk to 
    6. Determination of safety. Based on these risk assessments, EPA 
concludes that there is a reasonable certainty that no harm will result 
to the general population or to infants and children from aggregate 
exposure to cyproconazole residues.

IV. Other Considerations

A. Analytical Enforcement Methodology

    Adequate enforcement methodology (gas chromatograph/nitrogen-
phosphorus detection) is available to enforce the tolerance expression. 
The method may be requested from: Chief, Analytical Chemistry Branch, 
Environmental Science Center, 701 Mapes Rd., Ft. Meade, MD 20755-5350; 
telephone number: (410) 305-2905; email address: 
[email protected].

B. International Residue Limits

    In making its tolerance decisions, EPA seeks to harmonize U.S. 
tolerances with international standards whenever possible, consistent 
with U.S. food safety standards and agricultural practices. EPA 
considers the international maximum residue limits (MRLs) established 
by the Codex Alimentarius Commission (Codex), as required by FFDCA 
section 408(b)(4). The Codex Alimentarius is a joint United Nations 
Food and Agriculture Organization/World Health Organization food 
standards program, and it is recognized as an international food safety 
standards-setting organization in trade agreements to which the United 
States is a party. EPA may establish a tolerance that is different from 
a Codex MRL; however, FFDCA section 408(b)(4) requires that EPA explain 
the reasons for departing from the Codex level. The Codex has not 
established a MRL for cyproconazole.

C. Revisions to Petitioned-for Tolerances

    The Agency is correcting the commodity terminology for peanut by 
establishing a tolerance for peanut, rather than peanut, nutmeat. In 
addition, the Agency has modified the levels for which tolerances are 
being established for peanut (0.03 to 0.01 ppm). Based on an analysis 
of the residue data using the OECD tolerance calculation procedures, 
the tolerance for peanut is based on the limit of quantitation (0.01 
ppm). Following exaggerated-rate applications of cyproconazole, average 
residues of

[[Page 37473]]

cyproconazole were below the limit of quantitation in/on peanut, meal, 
refined oil, and butter; therefore, processing factors could not be 
calculated. Accordingly, separate tolerances for residues of 
cyproconazole are not required for peanut, meal, refined oil, and 
peanut butter.
    Also, EPA has revised the tolerance expression for cyproconazole 40 
CFR 180.485 to clarify:
    1. That as provided in FFDCA section 408(a)(3), the tolerance 
covers metabolites and degradates of cyproconazole.
    2. That compliance with the specified tolerance levels is to be 
determined by measuring only the specific compounds mentioned in the 
tolerance expression.

V. Conclusion

    Therefore, tolerances are established for residues of 
cyproconazole, in or on peanut and peanut, hay at 0.01 and 6.0 ppm, 

VI. References

    The following is a listing of the documents that are specifically 
referenced in this rule.

1. J. Kidwell, et al., December 4, 2007. Cyproconazole: Fourth 
Report of the Cancer Assessment Review Committee PC Code: 128993.
2. Environmental Protection Agency. January 14, 2002. Guidance on 
Cumulative Risk Assessment of Pesticide Chemicals That Have a Common 
Mechanism of Toxicity.

VII. Statutory and Executive Order Reviews

    This final rule establishes tolerances under FFDCA section 408(d) 
in response to a petition submitted to the Agency. The Office of 
Management and Budget (OMB) has exempted these types of actions from 
review under Executive Order 12866, entitled ``Regulatory Planning and 
Review'' (58 FR 51735, October 4, 1993). Because this final rule has 
been exempted from review under Executive Order 12866, this final rule 
is not subject to Executive Order 13211, entitled ``Actions Concerning 
Regulations That Significantly Affect Energy Supply, Distribution, or 
Use'' (66 FR 28355, May 22, 2001) or Executive Order 13045, entitled 
``Protection of Children from Environmental Health Risks and Safety 
Risks'' (62 FR 19885, April 23, 1997). This final rule does not contain 
any information collections subject to OMB approval under the Paperwork 
Reduction Act (PRA) (44 U.S.C. 3501 et seq.), nor does it require any 
special considerations under Executive Order 12898, entitled ``Federal 
Actions to Address Environmental Justice in Minority Populations and 
Low-Income Populations'' (59 FR 7629, February 16, 1994).
    Since tolerances and exemptions that are established on the basis 
of a petition under FFDCA section 408(d), such as the tolerance in this 
final rule, do not require the issuance of a proposed rule, the 
requirements of the Regulatory Flexibility Act (RFA) (5 U.S.C. 601 et 
seq.), do not apply.
    This final rule directly regulates growers, food processors, food 
handlers, and food retailers, not States or tribes, nor does this 
action alter the relationships or distribution of power and 
responsibilities established by Congress in the preemption provisions 
of FFDCA section 408(n)(4). As such, the Agency has determined that 
this action will not have a substantial direct effect on States or 
tribal governments, on the relationship between the national government 
and the States or tribal governments, or on the distribution of power 
and responsibilities among the various levels of government or between 
the Federal Government and Indian tribes. Thus, the Agency has 
determined that Executive Order 13132, entitled ``Federalism'' (64 FR 
43255, August 10, 1999) and Executive Order 13175, entitled 
``Consultation and Coordination with Indian Tribal Governments'' (65 FR 
67249, November 9, 2000) do not apply to this final rule. In addition, 
this final rule does not impose any enforceable duty or contain any 
unfunded mandate as described under Title II of the Unfunded Mandates 
Reform Act of 1995 (UMRA) (2 U.S.C. 1501 et seq.).
    This action does not involve any technical standards that would 
require Agency consideration of voluntary consensus standards pursuant 
to section 12(d) of the National Technology Transfer and Advancement 
Act of 1995 (NTTAA) (15 U.S.C. 272 note).

VIII. Congressional Review Act

    Pursuant to the Congressional Review Act (5 U.S.C. 801 et seq.), 
EPA will submit a report containing this rule and other required 
information to the U.S. Senate, the U.S. House of Representatives, and 
the Comptroller General of the United States prior to publication of 
the rule in the Federal Register. This action is not a ``major rule'' 
as defined by 5 U.S.C. 804(2).

List of Subjects in 40 CFR Part 180

    Environmental protection, Administrative practice and procedure, 
Agricultural commodities, Pesticides and pests, Reporting and 
recordkeeping requirements.

    Dated: June 11, 2013.
Lois Rossi,
Director, Registration Division, Office of Pesticide Programs.

    Therefore, 40 CFR chapter I is amended as follows:


1. The authority citation for part 180 continues to read as follows:

    Authority:  21 U.S.C. 321(q), 346a and 371.

2. Section 180.485 is amended as follows:
a. Revise paragraph (a)(1) introductory text.
b. Add alphabetically the entries ``peanut'' and ``peanut, hay'' to the 
table in paragraph (a)(1).
c. Revise paragraph (a)(2) introductory text.
d. Revise paragraph (a)(3) introductory text.
    The amendments read as follows:

Sec.  180.485  Cyproconazole; tolerances for residues.

    (a) * * * (1) Tolerances are established for residues of the free 
and conjugated forms of the fungicide cyproconazole, including its 
metabolites and degradates, in or on the commodities in the table 
below. Compliance with the proposed tolerance levels specified below is 
to be determined by measuring only cyproconazole ([alpha]-(4-
in or on the following commodities:

                                                             Parts per
                        Commodity                             million
                                * * * * *
Peanut..................................................            0.01
Peanut, hay.............................................            6.0
                                * * * * *

* * * * *
    (2) A tolerance is established for the combined residues of the 
free and conjugated forms of the fungicide cyproconazole, including its 
metabolites and degradates, in or on the commodity in the table below. 
Compliance with the tolerance level specified below is to be determined 
by measuring only the sum of cyproconazole ([alpha]-(4-chlorophenyl)-
[alpha]-(1-cyclopropylethyl)-1H-1,2,4-triazole-1-ethanol) and its 
metabolite [delta]-(4-chlorophenyl)-[beta],[delta]-dihydroxy-[gamma]-
methyl-1H-1,2,4-triazole-1-hexenoic acid, calculated as the 
stoichiometric equivalent of cyproconazole, in or on the following 
* * * * *

[[Page 37474]]

    (3) Tolerances are established for the combined residues of the 
free and conjugated forms of the fungicide cyproconazole, including its 
metabolites and degradates, in or on the commodities in the table 
below. Compliance with the tolerance level specified below is to be 
determined by measuring only the sum of cyproconazole ([alpha]-(4-
and its metabolite 2-(4-chlorophenyl)-3-cyclopropyl-1-[1,2,4]triazol-1-
yl-butane-2,3-diol, calculated as the stoichiometric equivalent of 
cyproconazole, in or on the following commodities:
* * * * *
[FR Doc. 2013-14914 Filed 6-20-13; 8:45 am]