Mancozeb; Pesticide Tolerances, 50902-50914 [2010-20453]

Agencies

• ENVIRONMENTAL PROTECTION AGENCY

[Federal Register Volume 75, Number 159 (Wednesday, August 18, 2010)]
[Rules and Regulations]
[Pages 50902-50914]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2010-20453]


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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[EPA-HQ-OPP-2005-0541; FRL-8841-1]


Mancozeb; Pesticide Tolerances

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

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SUMMARY: This regulation establishes tolerances for residues of 
mancozeb in or on multiple commodities which are identified and 
discussed later in this document. The Interregional Research Project 
Number 4 (IR-4) requested these tolerances under the Federal Food, 
Drug, and Cosmetic Act (FFDCA). In addition, this action establishes a 
time-limited tolerance for residues of mancozeb in or on walnuts in 
response to the approval of a specific exemption under section 18 of 
the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) 
authorizing the use of mancozeb on walnuts to control walnut blight. 
This regulation establishes a maximum permissible level of residues of 
mancozeb in walnuts. The time-limited tolerance on walnuts expires and 
is revoked on December 31, 2013. Also, this action revises the 
introductory text of paragraphs (a) and (b).

DATES: This regulation is effective August 18, 2010. Objections and 
requests for hearings must be received on or before October 18, 2010, 
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: EPA has established a docket for this action under docket 
identification (ID) number EPA-HQ-OPP-2005-0541. All documents in the 
docket are listed in the docket index available at https://www.regulations.gov. Although listed in the index, some information is 
not publicly available, e.g., Confidential Business Information (CBI) 
or other information whose disclosure is restricted by statute. Certain 
other material, such as copyrighted material, is not placed on the 
Internet and will be publicly available only in hard copy form. 
Publicly available docket materials are available in the electronic 
docket at https://www.regulations.gov, or, if only available in hard 
copy, at the OPP Regulatory Public Docket in Rm. S-4400, One Potomac 
Yard (South Bldg.), 2777 S. Crystal Dr., Arlington, VA. The Docket 
Facility is open from 8:30 a.m. to 4 p.m., Monday through Friday, 
excluding legal holidays. The Docket Facility telephone number is (703) 
305-5805.

FOR FURTHER INFORMATION CONTACT: Andrew Ertman, Registration Division 
(7505P), Office of Pesticide Programs, Environmental Protection Agency, 
1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone 
number: (703)308-9367; e-mail address: ertman.andrew@epa.gov.

SUPPLEMENTARY INFORMATION:

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. 
Potentially affected entities may include, but are not limited to those 
engaged in the following activities:
     Crop production (NAICS code 111).
     Animal production (NAICS code 112).
     Food manufacturing (NAICS code 311).
     Pesticide manufacturing (NAICS code 32532).
    This listing is not intended to be exhaustive, but rather to 
provide a guide for readers regarding entities likely to be affected by 
this action. Other types of entities not listed in this unit could also 
be affected. The North American Industrial Classification System 
(NAICS) codes have been provided to assist you and others in 
determining whether this action might apply to certain entities. If you 
have any questions regarding the applicability of this action to a 
particular entity, consult the person listed under FOR FURTHER 
INFORMATION CONTACT.

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 e-CFR site at https://www.gpoaccess.gov/ecfr

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-2005-0541 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 
October 18, 2010. 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 that does not contain any 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 a copy of 
your non-CBI objection or hearing request, identified by docket ID 
number EPA-HQ-OPP-2005-0541, by one of the following methods:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the on-line instructions for submitting comments.
     Mail: Office of Pesticide Programs (OPP) Regulatory Public 
Docket (7502P),

[[Page 50903]]

Environmental Protection Agency, 1200 Pennsylvania Ave., NW., 
Washington, DC 20460-0001.
     Delivery: OPP Regulatory Public Docket (7502P), 
Environmental Protection Agency, Rm. S-4400, One Potomac Yard (South 
Bldg.), 2777 S. Crystal Dr., Arlington, VA. Deliveries are only 
accepted during the Docket Facility's normal hours of operation (8:30 
a.m. to 4 p.m., Monday through Friday, excluding legal holidays). 
Special arrangements should be made for deliveries of boxed 
information. The Docket Facility telephone number is (703) 305-5805.

II. Summary of Petitioned-For Tolerance

    In the Federal Register of March 15, 2006 (71 FR 13389) (FRL-7767-
3), EPA issued a notice pursuant to section 408(d)(3) of FFDCA, 21 
U.S.C. 346a(d)(3), announcing the filing of pesticide petitions (PP 
3E4173, 5E4570, 9E5054, and 9E5061) by the Interregional Research 
Project Number 4 (IR-4), 681 US Highway No. 1 South, North Brunswick, 
NJ 08902-3390. The petitions requested that 40 CFR 180.176 be amended 
by establishing tolerances for residues of the fungicide mancozeb, zinc 
manganese ethylenebis dithiocarbamate, in or on the following 
commodities: (PP 3E4173) cucurbit vegetable crop group 9 at 4.0 parts 
per million (ppm); (PP 5E4570) mango, star apple (caimito), canistel, 
mamey sapote, sapodilla, and white sapote at 15.0 ppm; (PP 9E5054) 
ginseng at 2.0 ppm; (PP 9E5061) sugar apple, cherimoya, atemoya, 
custard apple, and sweetsop at 3.0 ppm. The notice included a summary 
of the petitions prepared by Dow AgroSciences, the registrant. However, 
in the Federal Register of September 16, 2009, (74 FR 47504) (FRL-8431-
4) in a document titled ``Mancozeb, Maneb, Metiram, and Thiram; 
Proposed Tolerance Actions,'' EPA proposed establishing tolerances for 
ginseng at 1.2 ppm, removing the existing tolerances for cucumber, 
melon and summer squash and establish a tolerance for the vegetable, 
cucurbit group 9 at 2.0 ppm, and revising the tolerance expression in 
Sec.  180.176. The reasons why EPA determined the tolerances for 
ginseng and cucurbit vegetable crop group 9 should be different from 
the original IR-4 petition as well as the rationale for changing the 
tolerance expression are explained in Unit V.D.
    EPA did not receive comments on the notice of March 15, 2006 but 
comments were received on the proposed rule of September 16, 2009. 
EPA's response to these comments is discussed in Unit V.C.
    EPA is not establishing a tolerance for sweetsop. The reason why is 
explained in Unit V.D.
    Separate from the actions being taken in response to the IR-4 
petitions, EPA is also establishing a time-limited tolerance for 
residues of mancozeb in or on walnuts at 0.015 ppm in connection with 
an emergency use of mancozeb approved under FIFRA. This tolerance 
expires and is revoked on December 31, 2013.

III. Emergency Exemption for Mancozeb on Walnuts and FFDCA Tolerances

    Walnut blight is a bacterial disease caused by Xanthomonas 
campestris pv.juglandis. It can result in severe economic losses due to 
undeveloped walnuts or early walnut-drop when the pathogen is present 
with free moisture during flowering and early nut development. 
Historically, walnut blight was managed by the application of copper 
products. Copper-resistant pathogens were found in some orchards and 
walnut losses in these orchards increased. Maneb was found to 
effectively manage walnut blight, and thus reduce walnut losses, where 
copper-resistant populations occurred and EPA has allowed use of maneb 
on walnut under an emergency exemption on a longstanding basis in the 
State of California. However, registrants have requested all products 
containing the active ingredient maneb be cancelled. Additionally, the 
Agency has been notified by the EBDC Task Force that there are no 
existing stocks of products containing maneb available for use on 
walnuts during 2010. Therefore, for the 2009-2010 growing season, the 
State of California requested an emergency exemption for use of 
mancozeb. This is the first time that California has requested mancozeb 
for this use. It represents an equivalent agricultural tool since 
mancozeb and maneb are related compounds.
    After having reviewed the submission, EPA determined that an 
emergency condition exists for California, and that the criteria for 
approval of an emergency exemption are met. EPA has authorized a 
specific exemption under FIFRA section 18 for the use of mancozeb on 
walnuts for control of walnut blight in California.
    As part of its evaluation of the emergency exemption application, 
EPA assessed the potential risks presented by residues of mancozeb in 
or on walnuts. In doing so, EPA considered the safety standard in 
section 408(b)(2) of FFDCA, and EPA decided that the necessary 
tolerance under section 408(l)(6) of FFDCA would be consistent with the 
safety standard and with FIFRA section 18. Consistent with the need to 
move quickly on the emergency exemption in order to address an urgent 
non-routine situation and to ensure that the resulting food is safe and 
lawful, EPA is issuing this tolerance without notice and opportunity 
for public comment as provided in section 408(l)(6) of FFDCA. Although 
this time-limited tolerance expires on December 31, 2013, under section 
408(l)(5) of FFDCA, residues of the pesticide not in excess of the 
amounts specified in the tolerance remaining in or on walnuts after 
that date will not be unlawful, provided the pesticide was applied in a 
manner that was lawful under FIFRA, and the residues do not exceed a 
level that was authorized by this time-limited tolerance at the time of 
that application. EPA will take action to revoke this time-limited 
tolerance earlier if any experience with, scientific data on, or other 
relevant information on this pesticide indicate that the residues are 
not safe.
    Because this time-limited tolerance is being approved under 
emergency conditions, EPA has not made any decisions about whether 
mancozeb meets FIFRA's registration requirements for use on walnuts or 
whether permanent tolerances for this use would be appropriate. Under 
these circumstances, EPA does not believe that this time-limited 
tolerance decision serves as a basis for registration of mancozeb by a 
State for special local needs under FIFRA section 24(c). Nor does this 
tolerance by itself serve as the authority for persons in any State 
other than California to use this pesticide on the applicable crops 
under FIFRA section 18 absent the issuance of an emergency exemption 
applicable within that State. For additional information regarding the 
emergency exemption for mancozeb, contact the Agency's Registration 
Division at the address provided under FOR FURTHER INFORMATION CONTACT.

IV. 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

[[Page 50904]]

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 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 section 408(b)(2)(D) of FFDCA, and the factors 
specified in section 408(b)(2)(D) of FFDCA, 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 mancozeb including 
exposure resulting from the tolerances established by this action.
    Mancozeb is a member of the ethylene bisdithiocarbamate (EBDC) 
group of fungicides that also includes the related active ingredients 
maneb and metiram. Mancozeb, maneb and metiram, are all metabolized to 
ethylenethiourea (ETU) in the body and all degrade to ETU in the 
environment. Therefore, EPA has considered the aggregate or combined 
risks from food, water and non-occupational exposure resulting from 
mancozeb alone and ETU from all sources (i.e., the other EBDC 
fungicides) for this action.
    EPA completed the Reregistration Eligibility Decision (RED) for 
mancozeb in September, 2005 (https://www.epa.gov/oppsrrd1/REDs/mancozeb_red.pdf). The Agency determined that most uses for the active 
ingredient mancozeb were eligible for reregistration provided that the 
risk mitigation measures identified in the RED were adopted and labels 
were amended to reflect these measures. Certain uses (foliar use on 
cotton, use on pineapple seed pieces, use on residential lawns/turf, 
use on athletic fields/turf, and use on pachysandra) were not eligible 
for reregistration and have since been voluntarily canceled by mancozeb 
registrants and deleted from all mancozeb labels.
    In assessing mancozeb risk for the RED, EPA included the uses 
associated with the petitions submitted by IR-4 to establish tolerances 
for residues of mancozeb on cucurbit vegetable crop group 9 (PP 
3E4173), mango, star apple, canistel, mamey sapote, sapodilla, white 
sapote (PP 5E4570), ginseng (PP 9E5054), sugar apple, cherimoya, 
atemoya, custard apple, and sweetsop (PP 9E5061). Additionally, EPA 
considered exposure to residues of mancozeb on walnut in connection 
with a pending petition (PP 5F4582) submitted by the registrant. No 
action was taken on these petitions until the mitigation measures 
outlined in the RED were implemented and existing stocks for the 
cancelled uses moved through the channels of trade. The registrant 
later withdrew the petition request to establish tolerances for 
mancozeb on walnuts.
    While these mitigation measures were being implemented several 
things changed regarding the mancozeb/ETU risk profile. First, EPA 
determined that it was appropriate to retain the 10X FQPA Safety Factor 
for acute dietary risk due to lack of the developmental neurotoxicity 
study. Second, the registrant submitted additional petitions in 2004 
that were not considered in the RED to establish tolerances for 
residues of mancozeb in or on almond (PP 4F4324), cabbage, leaf 
lettuce, peppers and broccoli (PP 4F4333). Therefore, based on these 
changes, EPA conducted an additional risk assessment in 2007 for 
mancozeb which assessed all uses (refer to risk assessment in the 
Docket EPA-HQ-OPP-2005-0541 titled ``Mancozeb: Human Health Risk 
Assessment to Support Proposed New Uses on Broccoli, Cabbage, Lettuce, 
Peppers and Almonds'').
    To date, EPA is still working to refine the risk assessment for ETU 
which incorporates the pending new uses for mancozeb that were 
submitted to EPA in 2004 (almond, cabbage, leaf lettuce, peppers and 
broccoli). In the meantime, EPA is moving forward to establish a time-
limited tolerance on walnut to support the emergency exemption as well 
as establish permanent tolerances for cucurbit vegetable group 9, 
mango, star apple, canistel, mamey sapote, sapodilla, white sapote, 
ginseng, sugar apple, cherimoya, atemoya, and custard apple. EPA is 
relying on an assessment conducted for mancozeb in 2007 (refer to risk 
assessment in the Docket EPA-HQ-OPP-2005-0541 titled ``Mancozeb: Human 
Health Risk Assessment to Support Proposed New Uses on Broccoli, 
Cabbage, Lettuce, Peppers and Almonds''), an assessment for ETU from 
2007 (for short- and intermediate-term aggregate exposures; refer to 
risk assessment in the Docket EPA-HQ-OPP-2005-0541 titled 
``Ethylenethiourea (ETU) from EBDCs: Health Effects Division (HED) 
Human Health Risk Assessment of the Common Metabolite/Degradate ETU''), 
and the assessment completed in the RED for exposures to ETU since that 
is still valid and accounts for exposure to all of the commodities 
discussed in this rule (refer to risk assessment in the Docket EPA-HQ-
OPP-2005-0176 titled ``ETU from EBDCs: Health Effects Division (HED) 
Human Health Risk Assessment of the Common Metabolite/Degradate ETU to 
Support Reregistration''). Since the 2007 ETU assessment includes the 
use on almond, cabbage, leaf lettuce, peppers and broccoli, uses for 
which tolerances do not exist and are not being established at this 
time, the estimates for short- and intermediate-term aggregate risk for 
ETU are likely overestimates.
    It is also important to note that since most products for maneb 
have been cancelled or will be shortly and there are limited existing 
stocks for maneb still in the channels of trade, the risk assessments 
for ETU likely overestimate the exposures to this common metabolite. 
Additionally, the risk estimates for mancozeb include uses for which 
tolerances do not exist and are not being established at this time, and 
therefore, the numbers reported are an over estimate of the potential 
risks.
    EPA's assessment of exposures and risks associated with mancozeb 
and ETU follows.

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 
children. In addition to evaluating mancozeb, EPA also evaluated the 
risks of ETU, a contaminant, metabolite and degradation product of 
mancozeb and the other EBDC group of fungicides, which includes the 
related active ingredients metiram and maneb.
    1. Mancozeb. Mancozeb is not acutely toxic via the oral, dermal or 
inhalation routes of exposure. Further, mancozeb is not a skin irritant 
nor is it a skin sensitizer, although it does cause mild eye 
irritation. The findings in multiple studies demonstrate that the 
thyroid is a target organ for mancozeb. Thyroid toxicity was manifested 
as alternations in thyroid hormones, increased thyroid weight, and 
microscopic thyroid lesions (mainly thyroid follicular cell 
hyperplasia). These effects are due to the ETU metabolite. In a 
subchronic study in the rat, neuropathology was seen (injury to 
peripheral nerves) microscopically with associated clinical signs 
(abnormal gait and limited use of rear legs) and loss of muscle mass. 
An acute neurotoxicity study with mancozeb has been completed and

[[Page 50905]]

reviewed since the last risk assessment; neuropathology was not 
observed, and minimal effects upon motor activity were observed at high 
doses. The Agency conducted a preliminary dietary assessment using a 
point-of-departure from this study and found no risk concerns. Other 
toxicity included increases in bilateral retinopathy in the chronic rat 
study. Elevated cholesterol and a mild, regenerative, anemia occurred 
in subchronic and chronic dog studies.
    Mancozeb is rapidly absorbed and eliminated in the urine. In oral 
rat metabolism studies with radiolabelled mancozeb and other EBDCs, an 
average 7.5% in vivo metabolic conversion of EBDC to ETU occurred, on a 
weight-to-weight basis. Metabolism data indicate mancozeb does not bio-
accumulate. Mancozeb has been tested in a series of in vitro and in 
vivo genotoxicity assays, which have shown that it exhibits weak 
genotoxic potential.
    Thyroid follicular cell adenomas and carcinomas were increased in 
high-dose males and females in the combined rat toxicity/
carcinogenicity study with mancozeb. Doses in a mouse study were too 
low to assess carcinogenicity, and there were no treatment-related 
changes in tumor rates. Historically, mancozeb's potential for 
carcinogenicity has been based on its metabolite ETU, which is 
classified as a probable human carcinogen. However, since ETU is known 
to be the chemical causing the thyroid tumors observed, the cancer 
assessment has been done only for ETU rather than the parent compound.
    Developmental defects in the rat developmental toxicity study 
included hydrocephaly, skeletal system defects, and other gross defects 
which occurred at a dose causing maternal mortality and did not 
indicate increased susceptibility of offspring. Abortions occurred in 
the rabbit developmental toxicity study at the high dose which also 
caused maternal mortality, and there was no indication of enhanced 
susceptibility of offspring in the rabbit. There was no evidence of 
reproductive toxicity in the 2-generation reproduction study in rats.
    2. ETU. The thyroid is a target organ for ETU; thyroid toxicity in 
subchronic and chronic rat, mouse, and dog studies included decreased 
levels of T4, increases or decreases in T3, compensatory increases in 
levels of TSH, increased thyroid weight, and microscopic thyroid 
changes, chiefly hyperplasia. Overt liver toxicity was observed in one 
chronic dog study. ETU is classified as a probable human carcinogen 
based on liver tumors in female mice.
    Developmental defects in the rat developmental study were similar 
to those seen with mancozeb, and included hydrocephaly and related 
lesions, skeletal system defects, and other gross defects. These 
defects showed increased susceptibility to fetuses because they 
occurred at a dose which only caused decreased maternal food 
consumption and body weight gain.
    Specific information on the studies received and the nature of the 
toxic effects caused by mancozeb as well as the no-observed-adverse-
effect-level (NOAEL) and the lowest-observed-adverse-effect-level 
(LOAEL) from the toxicity studies can be found at www.regulations.gov 
in the document titled ``Mancozeb: Human Health Risk Assessment to 
Support Proposed New Uses on Broccoli, Cabbage, Lettuce, Peppers and 
Almonds,'' pp. 13-15 in docket ID number EPA-HQ-OPP-2005-0541.
    Additionally, specific information on the studies received and the 
nature of the toxic effects caused by ETU as well as the NOAEL and the 
LOAEL from the toxicity studies can be found at www.regulations.gov in 
document titled ``ETU from EBDCs: Health Effects Division (HED) Human 
Health Risk Assessment of the Common Metabolite/Degraduate ETU to 
Support Reregistration. Chemical ID No. 600016. DP Barcode No. 
D305129,'' pp. 9-11 in docket ID number EPA-HQ-OPP-2004-0078.

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 https://www.epa.gov/pesticides/factsheets/riskassess.htm.
    A summary of the toxicological endpoints for mancozeb and ETU used 
for human risk assessment is shown in Tables 1 and 2 of this unit.

   Table 1.--Summary of Toxicological Doses and Endpoints for Mancozeb for Use in Human Health Risk Assessment
----------------------------------------------------------------------------------------------------------------
                                        Point of Departure and
          Exposure/Scenario               Uncertainty/Safety     RfD, PAD, LOC for Risk  Study and Toxicological
                                               Factors                 Assessment                Effects
----------------------------------------------------------------------------------------------------------------
Acute dietary                          NOAEL = 128 milligrams/  Acute RfD = 0.13 mg/kg/  Developmental Toxicity
(Females 13-50 years of age).........   kilograms/day (mg/kg/    day                      in the rat
                                        day)                    Acute PAD = 0.13 mg/kg/  LOAEL = 512 mg/kg/day
                                       UFA =10x...............   day.                     based on hydrocephaly
                                       UFH = 10x..............                            and other
                                       UFDB=10x...............                            malformations
----------------------------------------------------------------------------------------------------------------
Acute dietary                              No appropriate endpoint was identified from oral toxicity studies.
(General population including infants
 and children).
----------------------------------------------------------------------------------------------------------------

[[Page 50906]]

 
Chronic dietary                        NOAEL= 4.83 mg/kg/day    Chronic RfD = 0.005 mg/  Toxicity/
(All populations)....................  UFA = 10x..............   kg/day                   Carcinogenicity in the
                                       UFH = 10x..............  Chronic PAD = 0.005 mg/   rat
                                       UFDB=10x...............   kg/day.                 LOAEL = 30.9 mg/kg/day
                                                                                          based thyroid toxicity
                                                                                          (changes in thyroid
                                                                                          hormone levels,
                                                                                          microscopic thyroid
                                                                                          changes and changes in
                                                                                          thyroid weights)
----------------------------------------------------------------------------------------------------------------
Incidental oral short- or              NOAEL= 9.24 mg/kg/day    LOC for MOE = 1,000      Subchronic Toxicity
 intermediate term                     UFA = 10x..............                            Study in the rat
(1 to 30 days).......................  UFH = 10x..............                           LOAEL = 17.82 mg/kg/day
                                       UFDB=10x...............                            based on decreased T4
----------------------------------------------------------------------------------------------------------------
Dermal short- and intermediate term    Mancozeb has low dermal absorption. No systemic toxicity observed via the
(1 to 30 days).......................     dermal route at 1,000 mg/kg/day. Developmental effects were noted at
                                        doses much higher than those where systemic toxicity was observed in the
                                        maternal animals (in oral studies) indicating that developmental effects
                                            will not occur below 1,000 mg/kg/day the limit dose, from dermal
                                                                        exposure.
----------------------------------------------------------------------------------------------------------------
Dermal long-term                       Dermal (or oral) study   LOC for MOE = 1,000      Toxicity/
                                        NOAEL= 4.83 mg/kg/day                             Carcinogenicity in the
                                        (dermal absorption                                rat
                                        rate = 1%                                        LOAEL = 30.9 mg/kg/day
                                       UFA = 10x..............                            based on thyroid
                                       UFH = 10x..............                            toxicity (changes in
                                       UFDB=10................                            thyroid hormone
                                                                                          levels, microscopic
                                                                                          thyroid changes and
                                                                                          changes in thyroid
                                                                                          weights)
----------------------------------------------------------------------------------------------------------------
Inhalation short-, intermediate-, or   NOAEL = 0.079 mg/L       LOC for MOE = 1,000      Subchronic Inhalation
 long-term                              [equivalent to 21 mg/                             in the rat
                                        kg/day]                                          LOAEL = 0.326 mg/L
                                       UFA = 10x..............                            based on thyroid
                                       UFH = 10x..............                            hyperplasia and
                                       UFDB=10x...............                            decreased T4 (females)
----------------------------------------------------------------------------------------------------------------
Cancer                                  Mancozeb's potential for carcinogenicity is due to the formation of the
(Oral, dermal, inhalation)...........      metabolite ETU which is classified as a probable human carcinogen.
                                        Mancozeb's cancer risk is calculated by estimating exposure to mancozeb-
                                        derived ETU and using the ETU cancer potency factor (Q1*) of 6.01 x 10-2
                                               (mg/kg/day)-1 to provide a quantitative estimate of risk.
----------------------------------------------------------------------------------------------------------------
UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members
  of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. UFS = use of a short-term
  study for long-term risk assessment. UFDB = to account for the absence of data or other data deficiency. FQPA
  SF = Food Quality Protection Act Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD =
  reference dose. MOE = margin of exposure. LOC = level of concern.


     Table 2.--Summary of Toxicological Doses and Endpoints for ETU for Use in Human Health Risk Assessment
----------------------------------------------------------------------------------------------------------------
                                        Point of Departure and
          Exposure/Scenario               Uncertainty/Safety     RfD, PAD, LOC for Risk  Study and Toxicological
                                               Factors                 Assessment                Effects
----------------------------------------------------------------------------------------------------------------
Acute dietary                          NOAEL = 5 milligrams/    Acute RfD = 0.005 mg/kg/ Developmental Toxicity
 (Females 13-50 years of age)........   kilograms/day (mg/kg/    day                      in the rat (Khera
                                        day)                    Acute PAD = 0.005 mg/kg/  Study, MRID No.
                                       UFA = 10x..............   day.                     45937601)
                                       UFH = 10x..............                           LOAEL = 10 mg/kg/day
                                       UFDB=10x...............                            based on developmental
                                                                                          defects of the brain
----------------------------------------------------------------------------------------------------------------
Acute dietary                             No appropriate endpoint attributable to a single exposure (dose) was
(General population including infants                                  identified.
 and children).
----------------------------------------------------------------------------------------------------------------
Chronic dietary                        NOAEL= 0.18 mg/kg/day    Chronic RfD = 0.0002 mg/ Chronic Oral Toxicity
(All populations)....................  UFA = 10x..............   kg/day                   in the dog.
                                       UFH = 10x..............  Chronic PAD = 0.0002 mg/ LOAEL = 1.99 mg/kg/day
                                       UFDB= 10x..............   kg/day.                  based on thyroid
                                                                                          toxicity (increased
                                                                                          thyroid weight and
                                                                                          macroscopic changes in
                                                                                          the thyroid -
                                                                                          hypertrophy,
                                                                                          follicular dilation)
----------------------------------------------------------------------------------------------------------------
Incidental Oral (Short- and            NOAEL= 7 mg/kg/day       Residential LOC = 1,000  4 week range-finding
 Intermediate-Term)                    UFA = 10x..............                            dog study
                                       UFH = 10x..............                           LOAEL = 34 mg/kg/day
                                       UFDB=10x...............                            based on thyroid
                                                                                          toxicity (decreased
                                                                                          levels of thyroid
                                                                                          hormones, gross
                                                                                          thyroid lesions)
----------------------------------------------------------------------------------------------------------------

[[Page 50907]]

 
Dermal (Short- and Intermediate-Term)  NOAEL = 5 mg/kg/day      LOC for MOE = 1,000      Developmental Toxicity
                                       DA = 26%...............                            in the rat (Khera
                                       UFA = 10x..............                            Study, MRID No.
                                       UFH = 10x..............                            45937601)
                                       UFDB= 10x..............                           LOAEL = 10 mg/kg/day
                                                                                          based on developmental
                                                                                          defects of the brain
----------------------------------------------------------------------------------------------------------------
Dermal (Long-Term)                     NOAEL = 0.18 mg/kg/day   LOC for MOE = 1,000      Chronic Oral Toxicity
                                       DA = 26%...............                            in the dog
                                       UFA = 10x..............                           LOAEL = 1.99 mg/kg/day
                                       UFH = 10x..............                            based on thyroid
                                       UFDB= 10x..............                            toxicity (increased
                                                                                          thyroid weight and
                                                                                          macroscopic changes in
                                                                                          the thyroid -
                                                                                          hypertrophy,
                                                                                          follicular dilation)
----------------------------------------------------------------------------------------------------------------
Inhalation (Short- and Intermediate-   Inhalation (or oral)     LOC for MOE = 1,000      Developmental Toxicity
 Term)                                  study NOAEL= 5 mg/kg/                             in the rat (Khera
                                        day                                               Study, MRID No.
                                       UFA = 10x..............                            45937601)
                                       UFH = 10x..............                           LOAEL = 10 mg/kg/day
                                       UFDB= 10x..............                            based on developmental
                                       Inhalation toxicity is                             defects of the brain
                                        assumed to be
                                        equivalent to oral
                                        toxicity..
----------------------------------------------------------------------------------------------------------------
Inhalation (Long-Term)                 NOAEL = 0.18 mg/kg/day   LOC for MOE = 1,000      Chronic Oral Toxicity
                                       UFA = 10x..............                            in the dog
                                       UFH = 10x..............                           LOAEL = 1.99 mg/kg/day
                                       UFDB= 10x..............                            based on thyroid
                                       Inhalation toxicity is                             toxicity (increased
                                        assumed to be                                     thyroid weight and
                                        equivalent to oral                                macroscopic changes in
                                        toxicity..                                        the thyroid -
                                                                                          hypertrophy,
                                                                                          follicular dilation)
----------------------------------------------------------------------------------------------------------------
Cancer                                   Q1* = 6.01 x 10 -2 (mg/kg/day)-1ETU is classified as a probable human
(Oral, dermal, inhalation)...........        carcinogen. Cancer risk is quantitified with a linear low-dose
                                              extrapolation approach based on liver tumors in female mice.
----------------------------------------------------------------------------------------------------------------
UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members
  of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. UFS = use of a short-term
  study for long-term risk assessment. UFDB = to account for the absence of data or other data deficiency. FQPA
  SF = Food Quality Protection Act Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD =
  reference dose. MOE = margin of exposure. LOC = level of concern. DA = Dermal Absorption.

C. Exposure Assessment

    1. Dietary exposure from food and feed uses. In evaluating dietary 
exposure to mancozeb, EPA considered exposure under the petitioned-for 
tolerances discussed in this document including additional proposed 
uses that the Agency is not establishing tolerances for at this point 
(almonds, cabbage, lettuce, broccoli, and pepper) as well as all 
existing mancozeb tolerances in 40 CFR 180.176. In evaluating dietary 
exposure to ETU, EPA considered exposure under the petitioned-for 
tolerances discussed in this document as well as all existing uses of 
the EBDC group of fungicides (maneb, metiram, mancozeb). EPA assessed 
dietary exposures from mancozeb and ETU 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.
    The Dietary Exposure Evaluation Model (DEEM\(TM)\) analysis 
evaluated the individual food consumption as reported by respondents in 
the USDA 1994-1996 and 1998 Nationwide Continuing Surveys of Food 
Intake by Individuals (CSFII).
    a. Mancozeb. The following assumptions were made for the acute 
exposure assessments: The Agency conducted a highly refined, 
probabilistic acute dietary assessment incorporating maximum percent 
crop treated information for proposed uses that the Agency is not 
establishing tolerances at this time (almonds, cabbage, lettuce, 
broccoli, and pepper) and existing uses, field trial or monitoring 
data, and processing and cooking factors.
    b. ETU. The following assumptions were made for the acute exposure 
assessments: The Agency conducted a highly refined, probabilistic acute 
dietary assessment incorporating maximum percent crop treated 
information for new and existing uses, field trial or monitoring data, 
and processing and cooking factors. It was assumed that commodities 
would not be treated with more than one EBDC in a season, as there are 
label restrictions regarding treatment with multiple EBDCs. Percent 
crop treated was estimated by summing the percent crop treated for the 
individual EBDCs. For residue values, EPA used either market basket 
survey data or field trial data. For a few commodities mancozeb - 
derived ETU from mancozeb field trial data were used for both mancozeb 
and maneb because maneb field trial data were not available and 
application rates were sufficiently similar to estimate maneb-derived 
ETU values.
    ii. Chronic exposure. In conducting the chronic dietary exposure 
assessment EPA used the Dietary Exposure Evaluation Model software with 
the Food Commodity Intake Database (DEEM-FCID\TM\), which incorporates 
food consumption data as reported by respondents in the USDA 1994-1996 
and 1998 Nationwide Continuing Surveys of Food Intake by Individuals 
(CSFII).
    a. Mancozeb. The chronic dietary exposure and risk assessment for 
mancozeb (non-cancer and cancer) incorporated average values based 
either on field trial data or monitoring data and average percent crop 
treated data for proposed uses that the Agency is not

[[Page 50908]]

establishing tolerances at this time (almonds, cabbage, lettuce, 
broccoli, and pepper) and existing uses, as well as processing and 
cooking factors.
    b. ETU. Chronic anticipated residues were calculated from field 
trial or monitoring data for ETU. Averages of the field trial and 
market basket survey residues were used. EPA also used PCT data.
    iii. Cancer. EPA determines whether quantitative cancer exposure 
and risk assessments are appropriate for a food-use pesticide based on 
the weight of the evidence from cancer studies and other relevant data. 
Cancer risk is quantified using a linear or non-linear approach. If 
sufficient information on the carcinogenic mode of action is available, 
a threshold or non-linear approach is used and a cancer RfD is 
calculated based on an earlier non-cancer key event. If carcinogenic 
mode of action data are not available, or if the mode of action data 
determines a mutagenic mode of action, a default linear cancer slope 
factor approach is utilized.
    Mancozeb degrades and/or metabolizes to ETU which causes thyroid 
tumors; therefore, EPA has historically attributed mancozeb's 
carcinogenicity to the formation of ETU, which is classified as a 
probable human carcinogen . The Agency has used the cancer potency 
factor (Q1*) of 0.0601 (mg/kg/day)-1 for ETU (based on liver 
tumors in female mice) for risk assessment. Therefore, cancer risk from 
exposure to mancozeb has been calculated by estimating exposure to 
mancozeb-derived ETU and using the Q1* for ETU. The same approach has 
been taken for the other EBDCs. EPA's estimated exposure to mancozeb-
derived ETU included ETU residues found in food as well as ETU formed 
by metabolic conversion on parent mancozeb in the body (conversion rate 
of 0.075).
    EPA relied on the chronic exposure assessment in assessing cancer 
risk.
    iv. Anticipated residue and percent crop treated (PCT) information. 
Section 408(b)(2)(E) of FFDCA authorizes EPA to use available data and 
information on the anticipated residue levels of pesticide residues in 
food and the actual levels of pesticide residues that have been 
measured in food. If EPA relies on such information, EPA must require 
pursuant to FFDCA section 408(f)(1) that data be provided 5 years after 
the tolerance is established, modified, or left in effect, 
demonstrating that the levels in food are not above the levels 
anticipated. For the present action, EPA will issue such data call-ins 
as are required by FFDCA section 408(b)(2)(E) and authorized under 
FFDCA section 408(f)(1). Data will be required to be submitted no later 
than 5 years from the date of issuance of these tolerances.
    Section 408(b)(2)(F) of FFDCA states that the Agency may use data 
on the actual percent of food treated for assessing chronic dietary 
risk only if:
     Condition a: The data used are reliable and provide a 
valid basis to show what percentage of the food derived from such crop 
is likely to contain the pesticide residue.
     Condition b: The exposure estimate does not underestimate 
exposure for any significant subpopulation group.
     Condition c: Data are available on pesticide use and food 
consumption in a particular area, the exposure estimate does not 
understate exposure for the population in such area.
In addition, the Agency must provide for periodic evaluation of any 
estimates used. To provide for the periodic evaluation of the estimate 
of PCT as required by FFDCA section 408(b)(2)(F), EPA may require 
registrants to submit data on PCT.
    For mancozeb the Agency estimated the PCT for existing uses as 
follows:
    Cantaloupes 5%; pumpkins 5%; sugar beets 5%; tobacco 5%; cucumber 
10%; garlic 10%; sweet corn 10%; grapes 15%; squash 15%; asparagus 20%; 
eggplant 20%; tomatoes 25%; apples 30%; cranberries 30%; watermelons 
35%; pears 40%; onions 50%; and potatoes 54%. Beans, green; carrots; 
cherries; corn (field); cotton; oranges; peaches; peanuts; pecans; 
prunes, plums; strawberries; walnuts; and wheat all average less than 
1%.
    For ETU the Agency estimated the PCT for existing uses of mancozeb, 
maneb and metiram.
    a. Mancozeb. For mancozeb, the PCT was identical to that listed in 
this unit.
    b. Maneb. For maneb, the Agency estimated the PCT for existing uses 
as follows:
    Almonds 10%; apples 1%; dry beans 1%; green beans 5%; broccoli 5%; 
Brussels sprouts 21%; cabbage 15%; carrots 1%; cauliflower 5%; celery 
5%; collards 10%; field corn 1%; eggplant 55%; garlic 25%; grapes 1%; 
mustard greens 5%; kale 5%; lettuce 65%; onions; 10%; pears 1%; peppers 
30%; potatoes 5%; pumpkins 5%; spinach 15%; squash 5%; sugar beets 1%; 
sweet corn 1%; tomatoes 5%; walnuts 30%; watermelons 5%; wheat 5%.
    c. Metiram. For metiram, the Agency estimated the PCT for existing 
uses as follows:
    Apples 15%; asparagus 1%; peaches 1%; potatoes 10%; squash 1%.
    The PCT estimates for mancozeb and maneb on walnuts reflect usage 
of maneb on walnuts under an emergency exemption prior to the 
cancellation of maneb products and establishment of the emergency 
exemption use on walnuts for mancozeb. Going forward, EPA expects 
mancozeb use on walnuts to replace maneb. However, for this present 
action, EPA concludes it is reasonable to use the risk assessment that 
relied upon the PCT estimates in this unit for walnuts because: EPA 
does not expect mancozeb use on walnuts to be higher than the prior 
maneb use; mancozeb residues on walnuts and the consumption level of 
walnuts are insignificant compared to residue and consumption levels of 
other mancozeb-treated commodities (e.g., melons and apples); and ETU 
residues from maneb and macozeb are equivalent.
    In most cases, EPA uses available data from United States 
Department of Agriculture/National Agricultural Statistics Service 
(USDA/NASS), proprietary market surveys, and the National Pesticide Use 
Database for the chemical/crop combination for the most recent 6-7 
years. EPA uses an average PCT for chronic dietary risk analysis. The 
average PCT figure for each existing use is derived by combining 
available public and private market survey data for that use, averaging 
across all observations, and rounding to the nearest 5%, except for 
those situations in which the average PCT is less than one. In those 
cases, 1% is used as the average PCT and 2.5% is used as the maximum 
PCT. EPA uses a maximum PCT for acute dietary risk analysis. The 
maximum PCT figure is the highest observed maximum value reported 
within the recent 6 years of available public and private market survey 
data for the existing use and rounded up to the nearest multiple of 5%.
    The Agency believes that the three conditions discussed in Unit 
III.C.1.iv. have been met. With respect to Condition a, PCT estimates 
are derived from Federal and private market survey data, which are 
reliable and have a valid basis. The Agency is reasonably certain that 
the percentage of the food treated is not likely to be an 
underestimation. As to Conditions b and c, regional consumption 
information and consumption information for significant subpopulations 
is taken into account through EPA's computer-based model for evaluating 
the exposure of significant subpopulations including several regional 
groups. Use of this consumption information in EPA's risk assessment 
process ensures that EPA's exposure estimate does not understate 
exposure for any significant subpopulation group and allows the Agency 
to be reasonably certain that no regional population is exposed to

[[Page 50909]]

residue levels higher than those estimated by the Agency. Other than 
the data available through national food consumption surveys, EPA does 
not have available reliable information on the regional consumption of 
food to which mancozeb may be applied in a particular area.
    2. Dietary exposure from drinking water--i. Mancozeb. The Agency 
has determined that mancozeb is very short-lived in soil and water, and 
would not reach water used for human consumption whether from surface 
water or ground water.
    ii. ETU. ETU is highly water soluble, and may reach both surface 
and ground water under some conditions. The ETU surface water Estimated 
Drinking Water Concentrations (EDWCs) were generated using a combined 
monitoring/modeling approach. Results of a surface water monitoring 
study conducted by the ETU Task Force were used to refine the outputs 
of the Pesticide Root Zone Model /Exposure Analysis Modeling System 
(PRZM-EXAMS) models; the site/scenario modeled was application of an 
EBDC fungicide on peppers in Florida, and was chosen to produce the 
highest EDWC acute values. The ground water EDWC was detected in a 
Florida community water system intake in a targeted ground water 
monitoring study conducted by the EBDC task force from 1999 to 2003. 
Both these surface and ground water values represent upper-bound 
conservative estimates of the total ETU residual concentrations that 
might be found in surface water and ground water due to the use of the 
EBDC fungicides. The values are listed in Table 3 of this unit.

                                   Table 3.-- Surface and Ground Water Values.
----------------------------------------------------------------------------------------------------------------
                                                Acute                   Chronic                   Cancer
----------------------------------------------------------------------------------------------------------------
Surface Water EDWC                     0.1 to 25.2 ppb          0.10 ppb                 0.10 ppb
----------------------------------------------------------------------------------------------------------------
Ground Water EDWC                      0.21 ppb                 0.21 ppb                 0.21 ppb
----------------------------------------------------------------------------------------------------------------

    Based on the PRZM/EXAMS and monitoring studies, the EDWCs of ETU 
acute and chronic exposures are estimated to be 25.2 parts per billion 
(ppb), and 0.1 ppb, respectively for surface water. The EDWC for 
chronic exposure is estimated to be 0.21 ppb for ground water.
    Estimates of drinking water concentrations were directly entered 
into the dietary exposure model. For acute dietary risk assessment, the 
water concentration value of 25.2 ppb was used to assess the 
contribution to drinking water. For chronic dietary risk assessment of 
ETU, the water concentration of value 0.21 ppb was used to assess the 
contribution to drinking water. For cancer dietary risk assessment of 
ETU, the water concentration of value 0.21 ppb was used to assess the 
contribution to drinking water.
    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).
    i. Mancozeb. Mancozeb is currently registered for use on the 
following residential sites: Home gardens, golf courses, and sod farms 
(potential exposure to mancozeb is from residues remaining on 
transplanted turf). The Agency has determined that it is appropriate to 
aggregate chronic exposure through food with short- and intermediate-
term residential exposures to mancozeb.
    The two scenarios that were evaluated for mancozeb are the Short/
Intermediate-Term Home Garden Aggregate (Adult) which considers 
residential handler exposures (inhalation) to adult applicators 
combined with average food exposures and the Short/Intermediate-Term 
Treated Turf Aggregate (Toddler) which considers residential incidental 
oral exposures to toddlers combined with average food exposures. The 
only postapplication scenario for adults in contact with treated turf 
(golf courses) is via the dermal route of exposure. Since no dermal 
endpoints were selected for mancozeb, a quantitative risk assessment 
for this scenario is not required.
    ii. ETU. ETU non-dietary exposure is expected as a result of the 
registered uses of mancozeb and the other EBDCs on home gardens, golf 
courses and sod farms. For ETU, aggregate exposure sources include 
dietary food, drinking water, home gardening activities and golfing. 
The Agency has determined that it is appropriate to aggregate chronic 
exposure through food with short- and intermediate-term residential 
exposures to mancozeb.
    The three scenarios that were evaluated for ETU are the Short/
Intermediate-Term Home Garden Aggregate which combines handler 
exposures (inhalation and dermal) and post application garden exposures 
(dermal) plus average daily food and drinking water exposure for adults 
and post application garden exposures (dermal) plus average daily food 
and drinking water exposure for youth, the Short-Term Treated Turf 
Aggregate (Toddlers) which combines treated turf post application 
exposures (incidental oral and dermal) plus average daily food and 
drinking water exposure for toddlers and the Short/Intermediate-Term 
Treated Turf Aggregate (Adults ``Golfers'') which considers short-term 
residential exposures (dermal) plus average daily food and drinking 
water exposure for adults such as golfing on treated turf.
    Further information regarding EPA standard assumptions and generic 
inputs for residential exposures may be found at https://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.''
     As previously mentioned in Unit IV., the risk estimates summarized 
in this document are those that result only from the use of mancozeb, 
and ETU derived from mancozeb and the other EBDC chemicals, which are 
all dithiocarbamates. For the purposes of this action, EPA has 
concluded that mancozeb does not share a common mechanism of toxicity 
with other substances. The Agency reached this conclusion after a 
thorough internal review and external peer review of the data on a 
potential common mechanism of toxicity.
    EPA concluded that the available evidence does not support grouping 
the dithiocarbamates based on a common toxic effect (neuropathology) 
occurring by a common mechanism of toxicity (related to metabolism to 
carbon disulfide). After a thorough internal and external peer review 
of the existing data bearing on a common mechanism of toxicity, EPA 
concluded that the available evidence shows that neuropathology can not 
be linked with carbon disulfide formation. For more information, please 
see the December 19, 2001 memo, ``The Determination of Whether 
Dithiocarbamate Pesticides Share a Common Mechanism of Toxicity''on the 
internet at https://www.epa.gov/oppsrrd1/cumulative/dithiocarb.pdf.

[[Page 50910]]

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 
factor.
    2. Prenatal and postnatal sensitivity--i. Mancozeb. In the rat 
developmental study, developmental effects were observed in the 
presence of severe maternal effects, including maternal mortality and 
clinical signs. In the rabbit developmental study, developmental 
effects (spontaneous abortions) were observed at the same dose (80 mg/
kg/day) at which maternal effects included mortality and clinical 
signs. In the rat reproduction study, no effects were observed in 
offspring, while thyroid effects and body weight gain decrements 
occurred in adults.
    ii. ETU. There was evidence of increased susceptibility of fetuses 
to ETU in the rat developmental studies because hydrocephaly occurred 
at doses below that causing maternal toxicity. Acceptable reproductive 
and rabbit developmental toxicity studies were not available for ETU. 
As a result, the Agency evaluated the level of concern for the effects 
observed when considered in the context of all available toxicity data. 
In addition, the Agency evaluated the database to determine if there 
were residual uncertainties after establishing toxicity endpoints and 
traditional uncertainty factors to be used in the ETU risk assessment.
    3. Conclusion--i. Mancozeb. The toxicity database for mancozeb is 
not complete. The new requirement for an immunotoxicity study has not 
been met. The absence of an immunotoxicity study does not raise 
significant uncertainty. In the absence of that study, the available 
toxicity data for mancozeb have been thoroughly examined for any 
information which suggests a potential for immunotoxicity. The analysis 
did not reveal such information and the Agency does not believe that 
conducting the immunotoxicity study will result in a point of departure 
(POD) less than the currently selected PODs for risk assessment. A 
developmental neurotoxicity (DNT) study has been submitted, and EPA has 
recently completed a review of this study. Neurotoxicity was not 
observed in the study, and the young animals did not show 
susceptibility, as compared to the adults, for the slight toxicity that 
was observed (reduced body weight gain). Since the review of the DNT 
was completed after the most recent risk assessment was finished, EPA 
has not had the opportunity to re-evaluate the need for an FQPA factor. 
For this assessment, EPA has retained the presumptive 10X FQPA safety 
factor for the protection of children, but will re-visit the need for 
the safety factor for the next tolerance action.
    No additional FQPA Safety Factor is needed beyond the 10X database 
uncertainty factor applied to account for the data gap for a 
developmental neurotoxicity study with mancozeb. The reasons for this 
conclusion are:
     a. There is a lack of evidence of pre- and/or postnatal 
susceptibility resulting from exposure to mancozeb
    b. There are no residual uncertainties concerning toxicity, and
    c. The exposure assessment, although refined, is unlikely