[Federal Register Volume 62, Number 163 (Friday, August 22, 1997)]
[Rules and Regulations]
[Pages 44582-44595]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-22397]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Parts 180 and 186
[OPP-300541; FRL-5739-7]
RIN 2070-AB78
Thiodicarb; Pesticide Tolerance
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
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SUMMARY: This regulation establishes a tolerance for combined residues
of thiodicarb and its metabolite methomyl in or on broccoli, cabbage,
cauliflower, and leafy vegetables (except Brassica vegetables). The
petitioner, Rhone-Poulenc Ag Company, requested this tolerance under
the Federal Food, Drug and Cosmetic Act (FFDCA), as amended by the Food
Quality Protection Act of 1996 (FQPA) (Pub. L. 104-170).
DATES: This regulation is effective August 22, 1997. Objections and
requests for hearings must be received by EPA on or before October 22,
1997.
ADDRESSES: Written objections and hearing requests, identified by the
docket control number, [OPP-300541], must be submitted to: Hearing
Clerk (1900), Environmental Protection Agency, Rm. M3708, 401 M St.,
SW., Washington, DC 20460. Fees accompanying objections and hearing
requests shall be labeled ``Tolerance Petition Fees'' and forwarded to:
EPA Headquarters Accounting Operations Branch, OPP (Tolerance Fees),
P.O. Box 360277M, Pittsburgh, PA 15251. A copy of any objections and
hearing requests filed with the Hearing Clerk identified by the docket
control number, [OPP-300541], must also be submitted to: Public
Information and Records Integrity Branch, Information Resources and
Services Division (7506C), Office of Pesticide Programs, Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460. If you wish to
submit in person, bring a copy of objections and hearing requests to
Rm. 1132, CM #2, 1921 Jefferson Davis Hwy., Arlington, VA.
A copy of objections and hearing requests filed with the Hearing
Clerk may also be submitted electronically by
[[Page 44583]]
sending electronic mail (e-mail) to: opp-docket@epamail.epa.gov. Copies
of objections and hearing requests must be submitted as an ASCII file
avoiding the use of special characters and any form of encryption.
Copies of objections and hearing requests will also be accepted on
disks in WordPerfect 5.1 file format or ASCII file format. All copies
of objections and hearing requests in electronic form must be
identified by the docket control number [OPP-300541]. No Confidential
Business Information (CBI) should be submitted through e-mail.
Electronic copies of objections and hearing requests on this rule may
be filed online at many Federal Depository Libraries.
FOR FURTHER INFORMATION CONTACT: By mail: Thomas C. Harris,
Registration Division 7505C, Office of Pesticide Programs,
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460.
Office location, telephone number, and e-mail address: Crystal Mall #2,
1921 Jefferson Davis Hwy., Arlington, VA, (703) 305-5404, e-mail:
harris.thomas@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: In the Federal Register of March 5, 1997 (62
FR 10050)(FRL-5586-1) EPA issued a notice pursuant to section 408 of
the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(e)
announcing the filing of a pesticide petition (PP) for tolerance by
Rhone-Poulenc Ag Company, P.O. Box 12014, 2 T. W. Alexander Drive,
Research Triangle Park, NC 27709. There were no comments received in
response to the notice of filing.
The petition requested that 40 CFR 180.407 be amended by
establishing a tolerance for combined residues of the insecticide
thiodicarb (CAS number 59669-26-0, EPA chemical number 114501) and its
metabolite methomyl (CAS number 16752-77-5, EPA chemical number
090301), in or on broccoli at 7 parts per million (ppm), cabbage at 7
ppm, cauliflower at 7 ppm , and leafy vegetables (except Brassica
vegetables) at 35 ppm.
I. Risk Assessment and Statutory Findings
New section 408(b)(2)(A)(i) of the 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) 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)
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. . . .''
EPA performs a number of analyses to determine the risks from
aggregate exposure to pesticide residues. First, EPA determines the
toxicity of pesticides based primarily on toxicological studies using
laboratory animals. These studies address many adverse health effects,
including (but not limited to) reproductive effects, developmental
toxicity, toxicity to the nervous system, and carcinogenicity. Second,
EPA examines exposure to the pesticide through the diet (e.g., food and
drinking water) and through exposures that occur as a result of
pesticide use in residential settings.
A. Toxicity
1. Threshold and non-threshold effect. For many animal studies, a
dose response relationship can be determined, which provides a dose
that causes adverse effects (threshold effects) and doses causing no
observed effects (the ``no-observed effect level'' or ``NOEL'').
Once a study has been evaluated and the observed effects have been
determined to be threshold effects, EPA generally divides the NOEL from
the study with the lowest NOEL by an uncertainty factor (usually 100 or
more) to determine the Reference Dose (RfD). The RfD is a level at or
below which daily aggregate exposure over a lifetime will not pose
appreciable risks to human health. An uncertainty factor (sometimes
called a ``safety factor'') of 100 is commonly used since it is assumed
that people may be up to 10 times more sensitive to pesticides than the
test animals, and that one person or subgroup of the population (such
as infants and children) could be up to 10 times more sensitive to a
pesticide than another. In addition, EPA assesses the potential risks
to infants and children based on the weight of the evidence of the
toxicology studies and determines whether an additional uncertainty
factor is warranted. Thus, an aggregate daily exposure to a pesticide
residue at or below the RfD (expressed as 100 percent or less of the
RfD) is generally considered acceptable by EPA. EPA generally uses the
RfD to evaluate the chronic risks posed by pesticide exposure. For
shorter term risks, EPA calculates a margin of exposure (MOE) by
dividing the estimated human exposure into the NOEL from the
appropriate animal study. Commonly, EPA finds MOEs lower than 100 to be
unacceptable. This 100-fold MOE is based on the same rationale as the
100-fold uncertainty factor.
Lifetime feeding studies in two species of laboratory animals are
conducted to screen pesticides for cancer effects. When evidence of
increased cancer is noted in these studies, the Agency conducts a
weight of the evidence review of all relevant toxicological data
including short-term and mutagenicity studies and structure activity
relationship. Once a pesticide has been classified as a potential human
carcinogen, the appropriate risk assessment (e.g., linear low dose
extrapolations or MOE calculation based on the appropriate NOEL) will
be carried out based on the nature of the carcinogenic response and the
Agency's knowledge of its mode of action.
2. Differences in toxic effect due to exposure duration. The
toxicological effects of a pesticide can vary with different exposure
durations. EPA considers the entire toxicity data base, and based on
the effects seen for different durations and routes of exposure,
determines which risk assessments should be done to assure that the
public is adequately protected from any pesticide exposure scenario.
Both short and long durations of exposure are always considered.
Typically, risk assessments include ``acute'', ``short-term'',
``intermediate term'', and ``chronic'' risks. These assessments are
defined by the Agency as follows.
Acute risk, by the Agency's definition, results from 1-day
consumption of food and water, and reflects toxicity which could be
expressed following a single oral exposure to the pesticide residues.
High end exposure to food and water residues are typically assumed.
Short-term risk results from exposure to the pesticide for a period
of 1-7 days, and therefore overlaps with the acute risk assessment.
Historically, this risk assessment was intended to address primarily
dermal and inhalation exposure which could result, for example, from
residential pesticide applications. Since enaction of FQPA, this
assessment has been expanded. The assessment will only be performed
when there are primary dermal and inhalation exposures that result from
residential exposures lasting from 1-7 days. However, the analysis will
now address both dietary and non-dietary
[[Page 44584]]
sources of exposure, and will typically consider exposure from food,
water, and residential uses when reliable data are available. In a
short term assessment, risks from average food and water exposure, and
high-end residential exposure, are aggregated. High-end exposures from
all 3 sources are not typically added because of the very low
probability of this occurring in most cases, and because the other
conservative assumptions built into the assessment assure adequate
protection of public health. However, for cases in which high-end
exposure can reasonably be expected from multiple sources (e.g.
frequent and widespread homeowner use in a specific geographical area),
multiple high-end risks will be aggregated and presented as part of the
comprehensive risk assessment/characterization. Since the toxicological
endpoint considered in this assessment reflects exposure over a period
of at least 7 days, an additional degree of conservatism is built into
the assessment; i.e., the risk assessment nominally covers 1-7 days
exposure, and the toxicological endpoint/NOEL is selected to be
adequate for at least 7 days of exposure. (Toxicity results at lower
levels when the dosing duration is increased.)
Intermediate-term risk results from exposure for 7 days to several
months. This assessment is handled in a manner similar to the short-
term risk assessment.
Chronic risk assessment describes risk which could result from
several months to a lifetime of exposure. For this assessment, risks
are aggregated considering average exposure from all sources for
representative population subgroups including infants and children.
B. Aggregate Exposure
In examining aggregate exposure, FFDCA section 408 requires that
EPA take into account available and reliable information concerning
exposure from the pesticide residue in the food in question, residues
in other foods for which there are tolerances, residues in groundwater
or surface water that is consumed as drinking water, and other non-
occupational exposures through pesticide use in gardens, lawns, or
buildings (residential and other indoor uses). Dietary exposure to
residues of a pesticide in a food commodity are estimated by
multiplying the average daily consumption of the food forms of that
commodity by the tolerance level or the anticipated pesticide residue
level. The Theoretical Maximum Residue Contribution (TMRC) is an
estimate of the level of residues consumed daily if each food item
contained pesticide residues equal to the tolerance. In evaluating food
exposures, EPA takes into account varying consumption patterns of major
identifiable subgroups of consumers, including infants and children.
The TMRC is a ``worst case'' estimate since it is based on the
assumptions that food contains pesticide residues at the tolerance
level and that 100% of the crop is treated by pesticides that have
established tolerances. If the TMRC exceeds the RfD or poses a lifetime
cancer risk that is greater than approximately one in a million, EPA
attempts to derive a more accurate exposure estimate for the pesticide
by evaluating additional types of information (anticipated residue data
and/or percent of crop treated data) which show, generally, that
pesticide residues in most foods when they are eaten are well below
established tolerances.
Percent of crop treated estimates for thiodicarb used in this
tolerance assessment are derived from federal and private market survey
data. EPA considers these data reliable. A range of estimates are
supplied by this data and the upper end of this range is used for the
exposure assessment. By using this upper end estimate of percent of
crop treated, the Agency is reasonably certain that exposure is not
understated for any significant subpopulation. Further, regional
consumption information is taken into account through EPA's computer-
based model for evaluating the exposure of significant subpopulations,
including several regional groups, to pesticide residues. Review of
this regional data allows EPA to be reasonably certain that no regional
population is exposed to residue levels higher than those estimated by
the Agency. To provide for the periodic evaluation of these estimates
of percent crop treated, EPA will issue a data call-in under section
408(f) to all thiodicarb registrants for data on percent crop treated.
That data call-in will require such data to be submitted every 5 years
as long as the tolerances remain in force. For this pesticide, the most
highly exposed population subgroup (non-nursing infants <1 year="" old)="" for="" the="" methomyl="" aggregate="" chronic="" assessment="" was="" not="" regionally="" based.="" section="" 408(b)(2)(e)="" of="" the="" ffdca="" allows="" the="" agency="" to="" rely="" on="" anticipated="" or="" actual="" residue="" levels="" in="" establishing="" a="" tolerance,="" provided="" that="" the="" agency="" requires="" that="" data="" be="" provided="" 5="" years="" after="" the="" establishment="" of="" the="" tolerance,="" and="" thereafter="" as="" the="" agency="" deems="" appropriate,="" demonstrating="" that="" the="" residue="" levels="" are="" not="" above="" the="" levels="" relied="" upon.="" in="" establishing="" these="" tolerances="" for="" thiodicarb,="" the="" agency="" relied="" upon="" monte="" carlo="" simulations="" which="" relied="" upon="" anticipated="" or="" actual="" residue="" levels.="" in="" addition,="" one="" of="" the="" chronic="" assessments="" performed="" by="" novigen="" also="" utilized="" anticipated="" or="" actual="" residue="" levels.="" accordingly,="" the="" agency="" will="" require="" the="" submission="" of="" data="" pursuant="" to="" section="" 408(f)(1)="" of="" the="" ffdca="" so="" that="" the="" agency="" can="" determine="" 5="" years="" from="" the="" date="" these="" tolerances="" are="" established="" whether="" thiodicarb="" residues="" on="" food="" are="" below="" the="" levels="" relied="" upon="" in="" establishing="" these="" tolerances.="" ii.="" aggregate="" risk="" assessment="" and="" determination="" of="" safety="" consistent="" with="" 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="" thiodicarb="" and="" its="" metabolite="" methomyl="" and="" to="" make="" a="" determination="" on="" aggregate="" exposure,="" consistent="" with="" section="" 408(b)(2),="" for="" a="" tolerance="" for="" combined="" residues="" of="" thiodicarb="" and="" its="" metabolite="" methomyl="" on="" broccoli="" at="" 7="" ppm,="" cabbage="" at="" 7="" ppm,="" cauliflower="" at="" 7="" ppm,="" and="" leafy="" vegetables="" (except="" brassica="" vegetables)="" at="" 35="" ppm.="" epa's="" assessment="" of="" the="" dietary="" exposures="" and="" risks="" associated="" with="" establishing="" the="" tolerance="" follows.="" chemically,="" each="" thiodicarb="" molecule="" is="" made="" up="" of="" two="" methomyl="" molecules="" joined="" by="" a="" sulfur="" atom.="" plant="" metabolism="" studies="" show="" that="" thiodicarb="" is="" metabolized="" to="" methomyl,="" methomyl="" oxime,="" acetonitrile,="" and="" carbon="" dioxide.="" a="" ruminant="" animal="" metabolism="" study="" shows="" that="" thiodicarb="" is="" metabolized="" in="" steps="" to="" methomyl,="" methomyl="" oxime,="" acetonitrile,="" acetamide,="" acetic="" acid,="" and="" carbon="" dioxide.="" the="" breakdown="" to="" methomyl="" occurs="" more="" rapidly="" in="" plants="" and="" the="" environment="" than="" in="" animals.="" epa="" has="" determined="" that="" residues="" of="" acetamide,="" acetonitrile,="" methomyl="" oxime,="" acetic="" acid,="" and="" carbon="" dioxide="" resulting="" from="" the="" application="" of="" thiodicarb="" or="" methomyl="" are="" not="" residues="" of="" concern="" in="" animals="" and="" will="" not="" be="" regulated.="" the="" only="" residues="" of="" concern="" in="" plants="" and="" animals="" are="" thiodicarb="" and="" its="" primary="" metabolite="" methomyl.="" however,="" methomyl="" residues="" may="" result="" from="" the="" application="" of="" either="" thiodicarb="" or="" methomyl="" products.="" the="" following="" discussion="" addresses:="" 1.="" the="" toxicological="" properties="" of="" thiodicarb.="" 2.="" the="" toxicological="" properties="" of="" methomyl.="" 3.="" a="" food="" exposure="" and="" risk="" analysis="" for="" thiodicarb.="" [[page="" 44585]]="" 4.="" a="" drinking="" water="" exposure="" and="" risk="" analysis="" for="" methomyl="" (resulting="" from="" use="" of="" either="" thiodicarb="" or="" methomyl).="" 5.="" an="" aggregate="" (i.e.="" food="" +="" drinking="" water)="" exposure="" and="" risk="" analysis="" for="" methomyl="" (resulting="" from="" use="" of="" either="" thiodicarb="" or="" methomyl).="" there="" are="" no="" registered="" non-dietary="" (residential="" or="" non-occupational)="" uses="" of="" thiodicarb.="" therefore,="" there="" is="" no="" non-dietary="" exposure="" or="" risk="" associated="" with="" thiodicarb.="" 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.="" the="" nature="" of="" the="" toxic="" effects="" caused="" by="" thiodicarb="" and="" its="" metabolite="" methomyl="" are="" discussed="" below.="" 1.="" toxicological="" profile="" of="" technical="" thiodicarb--="" i.="" acute="" toxicity.="" in="" several="" acute="" oral="" toxicity="" studies="" with="" rats,="" the="">50 ranged from 46.5 mg/kg for males and 39.1 mg/kg for
females, which is Toxicity Category I, to 398 mg/kg for males and 248
mg/kg for females, which is Toxicity Category II (MRID 00025791,
00115604, 00115607). In a mouse study, the LD50 was 73 mg/kg
in males and 79 mg/kg in females (MRID 43784501).
The LD50 in an acute dermal toxicity study with rabbits
was found to be greater than 2,000 mg/kg. This is Toxicity Category III
(MRID 44025501).
In an acute inhalation toxicity study with rats, the
LC50 for males was 0.126 mg/L, for females 0.115 mg/L, and
greater than 0.32 mg/L for dust. These results are all considered to be
in Toxicity Category II (MRIDs 00041432 and 00045467.
Thiodicarb is a Toxicity Category III primary eye irritant in
rabbits. Instillation resulted in slight irritation (MRID 44025502).
Thiodicarb is a Toxicity Category IV primary dermal irritant in
rabbits (MRID 44025503) and thiodicarb induced a weak dermal
sensitization reaction in guinea pigs (MRIDs 41891004 and 43373201).
An acute delayed neurotoxicity study with thiodicarb in atropine-
pretreated hens, using a dose level of 660 mg/kg (LD50) was
negative (MRIDs 00044961 and 00053253). No data are available on the
acute and subchronic neurotoxicity of thiodicarb.
ii. Subchronic toxicity. In a subchronic toxicity study, Fisher 344
(COBS CD F/Crl BR) rats, 10/sex/group, were administered thiodicarb
(97% a.i.) via the diet at dose levels of 1, 3, 10, and 30 mg/kg/day
for 13 weeks. The NOEL was 3 mg/kg/day, and the Lowest Observed Effect
Level (LOEL) was 10 mg/kg/day, based on decreased body-weight gain,
decreased red blood cell (RBC) cholinesterase activity, and decreased
hemoglobin (MRID 00044965).
In a subchronic feeding study in Beagle dogs, thiodicarb was
administered via the diet at dose levels of 0, 15, 45, and 90 mg/kg/day
for 13 weeks. The high dose was lowered to 76 mg/kg/day in females
after day 36 due to the deaths of 2 high-dose females. The NOEL was 15
mg/kg/day, and the LOEL was 45 mg/kg/day, based on decreased RBC
parameters (RBCs, hematocrit and hemoglobin) in both sexes (MRID
00044966).
In another subchronic toxicity study in dogs, thiodicarb was
administered via the diet at dose levels of 0, 5, 15, and 45 mg/kg/day
for 6 months. The NOEL was 15 mg/kg/day, and the LOEL was 45 mg/kg/day,
based on liver effects of increased SGPT and increased liver weight
(MRID 00079474).
In a 21-day dermal toxicity study, New Zealand White rabbits were
administered thiodicarb via the skin at dose levels of 1,000, 2,000,
and 4,000 mg/kg/day for 6 hours a day, 5 days a week for 3 weeks. The
NOEL was 1,000 mg/kg/day, and the LOEL was 2,000 mg/kg/day, based on
macrocytic anemia, erythema, and edema (MRIDs 00043737 and 00044967).
In a 16-day dermal toxicity study, New Zealand white rabbits were
administered thiodicarb via the skin at dose levels of 1,000 and 4,000
mg/kg for 6 hours a day, 5 days a week for 3 consecutive weeks. The
NOEL was 1,000 mg/kg/day, and the LOEL was 4,000 mg/kg/day, based on
decreased erythrocytes, decreased hemoglobin, and decreased body weight
(MRID 00043738).
In a 9-day dust inhalation study, Sprague-Dawley rats were
administered thiodicarb particulates via the inhalation route at dose
levels of 0, 4.8, 17.7, and 59.5 mg/m3 for males, and 0,
4.8, 19.6, and 54.0 mg/m3 for females (mean measured
atmospheric concentrations) for 6 hours a day for 9 days. The NOEL was
not determined. At 4.8 mg/m3, two clinical signs typically
associated with cholinesterase effects (pinpoint pupils and tremors)
were observed in both sexes. There were no significant body-weight
effects at this dose level in either sex, and no statistically
significant effects were observed in any cholinesterase measurement
(plasma, RBC, and brain) at 4.8 or 17.7/19.6 mg/m3 in either
sex (MRIDs 00045467 and 00053252).
In a 4-week feeding study, CD-1 mice of both sexes were
administered thiodicarb via the diet at dose levels of; males 0, 6.2,
346, 734, and 1538 mg/kg/day, females 0, 8.3, 491, 954, and 2030 mg/kg/
day for 4 weeks. The NOEL was 6.2 and 8.3 mg/kg/day for males and
females respectively. The LOEL was 346 and 491 mg/kg/day for males and
females respectively. These results are based on increased liver weight
in females and increased spleen weight in both sexes (MRID 43611701).
In a subchronic feeding study, male and female Fischer 344 rats
were administered thiodicarb via the diet at dose levels of 0, 1, 3,
10, and 30 mg/kg/day for 28 days. The NOEL for effects on
cholinesterase activity was 10 mg/kg/day, and the LOEL was 30 mg/kg/
day, based on decreased plasma and RBC cholinesterase activity (MRID
00098292).
iii. Chronic toxicity and carcinogenicity. Beagle dogs were
administered technical thiodicarb via the diet at dose levels of 0, 164
(male 4.4/female 4.5 mg/kg/day), 487 (male 12.8/female 13.8 mg/kg/day),
and 1506 (male 38.3/female 39.5 mg/kg/day) ppm for one year. The NOEL
is male 4.4/female 4.5 mg/kg/day, and the LOEL is male 12.8/female 13.8
mg/kg/day, based on cholinesterase inhibition. The systemic NOEL is
male 12.8/female 13.8 mg/kg/day and the systemic LOEL is male 38.3/
female 39.5 mg/kg/day, based on reduced hematology parameters including
erythrocytes, hemoglobin, and hematocrit (MRID 00159813).
In a chronic toxicity/carcinogenicity study, Sprague-Dawley rats of
both sexes were administered thiodicarb via the diet at dose levels of
0 ppm, 60 ppm (male 3.3/female 4.5 mg/kg/day), 200 ppm (male 12/female
15 mg/kg), and 900 ppm (male 60/female 80 mg/kg) for 104 weeks. The
systemic NOEL was 60 ppm (male 3.3/female 4.5 mg/kg/day) and the LOEL
was 200 ppm (male 12/female 15 mg/kg/day), based on the increased
incidence of extramedullary hemopoiesis in males and decreased RBC
cholinesterase in females. There were no compound-related tumors
observed in the females. The high-dose males displayed an increased
incidence of interstitial cell tumors in the testes compared to the
concurrent control males, and the incidence was greater than the
historical control also (MRIDs 43308201, 43405001, 43596401).
In a carcinogenicity study, Charles River CD-1 mice of both sexes
were administered thiodicarb via the diet at dose levels of 0, 5, 70,
and 1,000 mg/kg/day for 97 weeks. The NOEL was 70 mg/
[[Page 44586]]
kg/day, and the LOEL was 1,000 mg/kg/day, based on increased mortality
in females, decreased body-weight gain in males, decreased hemoglobin,
hematocrit, and erythrocytes, increased alanine aminotransferase and
total bilirubin, increased liver and spleen weights, and increased
incidences of kidney, liver, and spleen lesions. In this study, the
administration of thiodicarb in the diet to CD-1 mice resulted in
increased incidences of hepatocellular tumors in both sexes. In both
male and female mice, there were statistically significant increases in
hepatocellular adenomas, carcinomas and combined adenomas/carcinomas at
the highest dose (1,000 mg/kg/day); there were also statistically
significant positive dose-related trends for adenomas and carcinomas,
alone and combined. The incidence of adenomas and carcinomas at the
highest dose exceeded that of historical controls in both sexes; in
addition, in male mice, the incidence of adenomas at the mid-dose (70
mg/kg/day) exceeded that of historical controls (MRIDs 43000501 and
43619301).
In another carcinogenicity study, Charles River CH:COBS CD-L
(ICR)BR mice of both sexes were administered thiodicarb via the diet at
dose levels of 1, 3, and 10 mg/kg/day for 104 weeks. The NOEL was 3 mg/
kg/day, and the LOEL was 10 mg/kg/day, based on mortality to thiodicarb
in females (MRID 00041407).
Thiodicarb is classified as a B2 - probable human carcinogen by the
Cancer Peer Review Committee (CPRC). The B2 classification was based on
statistically significant increases in hepatocellular adenomas,
carcinomas, and combined adenoma/carcinoma in both sexes of the CD-1
mouse and statistically significant increases in testicular
interstitial cell tumors in male Sprague-Dawley rats.
iv. Developmental toxicity. In a rat developmental toxicity study,
pregnant Charles River CD COBS rats were administered thiodicarb via
gavage on gestation days 6-19 at dose levels of 0 (vehicle 0.5%
methocel), 10, 20, and 30 mg thiodicarb/kg body weight/day. In another
rat developmental toxicity study, pregnant Fisher 344 rats were dosed
via the diet on (a) gestation days 6 to 15 or (b) gestation days 0-20
at dose levels of 0.5, 1.0, 3.0, and 100 mg thiodicarb (>99%)/kg body
weight/day. When these two studies are considered together, the
maternal toxicity NOEL is 10 mg/kg/day, and the maternal toxicity LOEL
is 20 mg/kg/day, based on clinical signs (tremors, inactivity). The
developmental toxicity NOEL is 3 mg/kg/day, and the LOEL is 10 mg/kg/
day, based on decreased fetal body weights and increased incidence of
litters and fetuses with developmental variations which included
unossification of sternebrae #5 and/or #6 and other sternebrae (MRIDs
00043739, 00043740, 00043741, 00053254, 00053255, 00053256).
In a developmental toxicity study, artificially-inseminated New
Zealand white rabbits were administered thiodicarb via gavage on
gestation days 6 through 19 at dose levels of 0 (vehicle, 0.5% aqueous
methylcellulose), 5, 20, and 40 mg/kg/day. The maternal toxicity NOEL
was 20 mg/kg/day, and the maternal toxicity LOEL was 40 mg/kg/day,
based on reduced body-weight gain and food consumption. The
developmental toxicity NOEL was 40 mg/kg/day, the highest dose tested
(MRIDs 00159814, 40280001).
In a developmental toxicity study, Charles River CD-1 mice were
administered thiodicarb on gestation days 6 through 16 via gavage at
dose levels of 0 (vehicle 0.5% methocel), 50, 100, and 200 mg
Thiodicarb/kg body weight/day. The maternal toxicity NOEL was 100 mg/
kg/day, and the maternal toxicity LOEL was 200 mg/kg/day, based on
increased mortality. The developmental toxicity NOEL was 200 mg/kg/day,
the highest dose tested (MRIDs 00043742, 00043743, 00053257, 00053258).
v. Reproductive toxicity. In a two-generation reproduction study,
Crl:CD BR/VAF/Plus rats were fed doses of 0, 5,
15, and 45 mg/kg/day of thiodicarb. The reproductive/developmental
toxicity NOEL is 5 mg/kg/day, and the reproductive/developmental
toxicity LOEL is 15 mg/kg/day, based on decreased fetal body weight and
viability. The systemic NOEL is 5 mg/kg/day and the systemic LOEL is 15
mg/kg/day, based on decreased body weight/gain and food consumption in
both sexes (MRIDs 42381301, 42381302, 42735101).
vi. Mutagenicity. Thiodicarb did not induce a mutagenic response in
the Ames assay, with or without metabolic activation (MRIDs 00044872,
00135792). Thiodicarb induced dose-related increased mutant frequencies
in mouse lymphoma TK +/- cells, with and without metabolic activation
and is considered to have an equivocal weak effect in the mouse
lymphoma forward mutation assay (MRID 00151574). Thiodicarb, with or
without metabolic activation, did not cause a clastogenic response in
the chromosomes of Chinese hamster ovary cells (MRID 00151572).
Thiodicarb is considered inactive in the primary rat hepatocyte
unscheduled DNA synthesis assay (MRID 00151573).
2. Toxicological profile of technical methomyl-- i. Acute toxicity.
The acute oral LD50 values for methomyl with rats were 34
and 30 mg/kg in males and females, respectively (Toxicity Category I).
Clinical signs observed in all treatment groups of both sexes included
tremors, low posture and salivation (MRID 42140101).
The dermal LD50 value for methomyl in rabbits was
greater than 2000 mg/kg (Toxicity Category III) for both sexes (MRID
42074602).
The acute inhalation LC50 for methomyl was 0.258 mg/L in
rats for both sexes (Toxicity Category II), based on a four-hour
exposure (nose only) to technical grade methomyl aerosol (MRID
42140102).
Methomyl is highly toxic via ocular exposure. In a primary eye
irritation study, a female rabbit treated with 15 mg of technical
methomyl (92.4%) died 20 minutes after the treatment with typical
cholinergic symptoms indicative of neurotoxicity. Animals treated with
10 mg of methomyl exhibited similar clinical signs of neurotoxicity but
survived. At this dose, corneal opacity and iritis were observed at 1
hour after the treatment and completely reversed by 7 days (MRID
41964001).
Another primary eye irritation study in rabbits using 30.5%
methomyl formulation showed corneal opacity and conjunctivitis from 7
to 14 days in washed and unwashed eyes, respectively. Primary eye
irritation for methomyl was considered to be in the Toxicity Category I
(MRID 00053407).
A primary dermal irritation study with technical methomyl in
rabbits showed no erythema or edema placing methomyl in Toxicity
Category IV (MRID 42074603).
A dermal sensitization study in guinea pigs using technical
methomyl showed that the compound is not a skin sensitizer (MRID
42074605).
ii. Subchronic toxicity. In a 90-day feeding study in rats, Charles
River CD rats (10/sex/group) were fed methomyl at dietary levels of 0,
10, 50 and 250 ppm (equivalent to 0, 0.5, 2.5 and 12.5 mg/kg/day,
respectively, based on the standard conversion ratio) for 13 weeks. An
additional group received 125 ppm (6.25 mg/kg/day) of the test material
for 6 weeks and 500 ppm (25 mg/kg/day) for the remaining 7 weeks.
Treatment did not cause increased mortalities. No inhibition of
cholinesterase activity was observed in any treated group. The NOEL is
125 ppm (6.25 mg/kg/day) and the LOEL is 250 ppm (12.5 mg/kg/day) based
on inhibited body weight gain in both sexes and erythroid hyperplasia
in the bone marrow of males (MRID 00007190).
[[Page 44587]]
In a 21-day dermal toxicity study, New Zealand White rabbits were
dermally exposed to methomyl (98.35%, a.i.) for 21 days at dose levels
of 0, 5, 50 or 500 mg/kg/day. Clinical signs included hyperactivity
(increased reaction to stimuli-noise) at the high-dose (both sexes). At
Day 21, mid- and high-dose males and high-dose females displayed
significantly lower plasma cholinesterase (ChE) activity. Mean RBC ChE
activity was also decreased, but only slightly, at the high-dose (both
sexes). Brain ChE activity was significantly decreased at the high-dose
(both sexes). At the mid-dose, although not statistically significant,
inhibition of brain ChE activity was indicated (3/5 males and 4/5
females exhibited brain ChE inhibition when compared with controls).
The NOEL for systemic toxicity is 5 mg/kg/day and the LOEL is 50 mg/kg/
day based on brain and plasma ChE inhibitions. No dermal irritation was
observed (MRID 41251501).
iii. Chronic toxicity and carcinogenicity. Sufficient data are
available to assess the chronic toxicity and carcinogenic potential of
methomyl. Methomyl has been classified as a ``Group E'', i.e. the
chemical is not likely to be carcinogenic to humans via relevant routes
of exposure (HED/RfD/Peer Review Report, October 25, 1996).
Combined chronic toxicity and carcinogenicity study in rats.
Charles River CD rats (80/sex/group) were fed diets containing methomyl
(99+%) for 2 years at dose levels of 0, 50, 100 and 400 ppm (0, 2.5,
5.0 and 20.0 mg/kg/day, respectively, based on the standard conversion
ratio). No significant toxicity was observed. The NOEL is 100 ppm (5
mg/kg/day) and the LOEL is 400 ppm (20 mg/kg/day) based on depressed
body weight gain. Methomyl was not considered carcinogenic because
there was no evidence that the test material increased the incidence of
any neoplastic lesion. Although the HED/RfD Review Committee accepted
the study, the Committee determined that the animals could have
tolerated higher doses than the highest dose level used (MRID
00078361).
Chronic toxicity study in dogs (2-year). Beagle dogs (4/sex/group)
were fed diets containing methomyl (90%) at dose levels of 0, 50, 100,
400 and 1,000 ppm (0, 1.25, 2.5, 10, and 25 mg/kg/day, respectively,
based on the standard conversion ratio) for 24 months. Two males at the
1,000 ppm group exhibited tremors, salivation, incoordination, and
circling movements during the 13th week of the study. One female in the
1,000 ppm group died in the 9th week of the study. A replaced dog
exhibited repeated convulsive seizures after 17 days of dosing and died
on day 18. There were no significant differences among treatment and
the control groups for RBC and plasma ChE activities which were
measured at week 9 and week 13 (high dose only) of the study. The NOEL
is 100 ppm (2.5 mg/kg/day) and the LOEL is 400 ppm (10.0 mg/kg/day)
based on histopathological effects in kidneys manifested as swollen/
irregular epithelial cells of the proximal convoluted tubules as well
as an increase in the amount of pigment in the cytoplasm of these cells
(MRID 00007091).
Carcinogenicity study in mice. CD-1 mice (80/sex/group) were fed
diets containing methomyl (99+%) initially at levels of 0, 50, 100 and
800 ppm (0, 7.5, 15 and 120 mg/kg/day, respectively, based on the
standard conversion ratio). Due to increased mortality, the high dose
level was decreased to 400 ppm at week 28; further, the high and mid
dose levels were reduced to 200 and 75 ppm, respectively, at week 39
for the same reason. These levels (50, 75 and 200 ppm) were maintained
for the remainder of the 104 week treatment period. The highest dose
level tested in this study was considered to be adequate for
carcinogenicity testing based on increased mortality. The treatment did
not alter the spontaneous tumor profile in this strain of mice under
the test conditions (MRID 00078423).
Other carcinogenic issues. It should be noted that methomyl is a
metabolite of and is structurally-related to thiodicarb, a pesticide
that was classified as a B2 carcinogen. In addition, acetamide, a
metabolite of methomyl, has been evaluated by the HED/CPRC and
classified as a Group C carcinogen, possible human carcinogen. However,
after a thorough investigation, the HED/RfD Review Committee concluded
that the ingestion of anticipated levels of methomyl and acetamide in
the diet should not represent a significant carcinogenic hazard to the
consuming public based on the following:
1. The conversion rate of methomyl to acetamide is low,
approximately 2-3 percent, therefore, residue levels of acetamide in
edible meat should be low.
2. Carcinogenicity studies with methomyl in two rodent species
indicated no increase in any type of tumor under the test conditions.
3. The product is comprised of 98.7 percent syn-isomer and 0.092
percent anti-isomer, syn-isomer must be converted to anti-isomer before
acetamide is formed.
4. Acetamide induced liver tumors in rats only when administered at
very high dosages, i.e. more than 1,000 mg/kg/day. (HED/RfD/Peer Review
Report, October 25, 1996).
iv. Developmental toxicity. Methomyl (99 - 100%) was administered
to 25 presumed pregnant Charles River-CD (ChR-CD) rats/group in the
diet at concentrations of 0, 50, 100 and 400 ppm (0, 4.9, 9.4 and 33.9
mg/kg/day) on gestation days 6 through 16. The data did not reveal any
apparent developmental toxicity. The NOEL for maternal toxicity is 100
ppm (9.4 mg/kg/day) and the LOEL is 400 ppm (33.9 mg/kg/day) based on
decreased body weight gain and food consumption during gestation. The
NOEL for developmental toxicity is 400 ppm (33.9 mg/kg/day) (MRID
00008621).
Methomyl (98.7%) was administered via stomach tube to 20 presumed
pregnant New Zealand white (DLI:NZW) rabbits per group (19 in the high-
dose group) at dosages of 0, 2, 6 and 16 mg/kg/day on gestation days 7
through 19. Clinical signs indicated neurotoxic effects in high-dose
rabbits. There was no evidence of developmental toxicity in this study.
The NOEL for developmental toxicity is 16 mg/kg/day. The NOEL for
maternal toxicity is 6 mg/kg/day and the LOEL is 16 mg/kg/day based on
mortalities and clinical signs (MRID 00131257).
v. Reproductive toxicity. Sprague-Dawley rats in the F0
parental generation were fed methomyl at dose levels of 0, 75, 600 or
1,200 ppm (0, 3.75, 30, or 60 mg/kg/day, respectively, based on the
standard conversion ratio). The F1 offspring were treated at
the same dosages. There was a dose-related increase in clinical signs
involving the nervous system during the first few weeks of the study
and the incidence of alopecia was increased in the 600 and 1,200 ppm
group animals. The NOEL for systemic toxicity is 75 ppm (3.75 mg/kg/
day) and the LOEL is 600 ppm (30 mg/kg/day) based on decreased body
weight and food consumption and altered hematology parameters. The NOEL
for reproductive toxicity is 75 ppm (3.75 mg/kg/day) and the LOEL is
600 ppm (30 mg/kg/day) based on decreases in both the mean number of
live pups and mean body weights of offspring (MRID 43250701).
vi. Mutagenicityy. Sufficient data are available to satisfy data
requirements for mutagenicity testing. Technical methomyl did not
induce a genotoxic response in any of the tests listed below.
Gene mutation. In a Chinese hamster ovary (CHO) cells HGPRT forward
gene mutation assay, methomyl was negative up to cytotoxic levels
(40 mM = 6.5
[[Page 44588]]
mg/mL -S9; 150 M = 0.24 mg/mL +S9) (MRID 00161887).
Chromosomal aberration assay. In a mouse micronucleus assay,
methomyl was negative in ICR mice up to an overtly toxic dose (12 mg/
kg) administered once by oral gavage. There was no evidence of a
cytotoxic effect on the target tissue (MRID 44047703). An in vivo bone
marrow cytogenetic assay indicated that the test was negative in
Sprague Dawley rats up to an overtly toxic level (20 mg/kg)
administered once by oral gavage. Target tissue cytotoxicity was not
observed (MRID 00161888).
Other genotoxic effects. Methomyl was found to be inactive in a
series of EPA-sponsored mutagenicity studies which included: Salmonella
typhimurium /Escherichia coli reverse gene mutation assays, DNA damage
studies in bacteria, yeast and human lung fibroblasts, and a Drosophila
melanogaster sex-linked recessive lethal assay (MRID 00124901).
vii. Neurotoxicity studies. An acute delayed neurotoxicity study
with methomyl in atropine-pretreated hens, using the LD50
dose (28 mg/kg) as well as higher doses, was negative (MRID 00008827).
No data are available on the acute and subchronic neurotoxicity of
methomyl in mammals. Since methomyl is a carbamate and neurotoxic signs
have been observed in two species (dogs and rabbits) by two different
exposure routes (oral and dermal, respectively), acute and subchronic
neurotoxicity studies are needed for a thorough investigation of this
parameter. A neurotoxicity screening battery (acute and subchronic) is
required to support the re-registration of this chemical.
B. Toxicological Endpoints
1. Acute toxicity-- i. Thiodicarb. For acute dietary exposure (1
day) the developmental NOEL of 3 mg/kg/day from a developmental
toxicity study in the rat is the endpoint to be used for risk
assessment for females 13+ years. This is based on skeletal variations
and decreases in pup body weights at 10 mg/kg/day. For the overall U.S.
population, and all other subgroups, the maternal NOEL of 10 mg/kg/day
is the endpoint to be used for risk assessment. This is based on the
clinical signs of tremors and inactivity at 20 mg/kg/day (LOEL).
For thiodicarb, EPA has decided that an MOE equal to or greater
than 100 is considered to be protective. Although there is a data gap
(acute neurotoxicity study), EPA has determined that this is simply a
confirmatory study. Other than this study, the database is complete.
While tremors and inactivity were observed in one developmental study,
other instances of neurotoxic behavior have not been observed in the
remaining studies.
ii. Methomyl. For acute dietary exposure (1 day) deaths in dams on
days 1-3 after dosing at 16 mg/kg/day (LOEL) from a developmental
toxicity study in rabbits (MRID# 00131257) was selected as the endpoint
for risk assessment. The maternal NOEL of 6 mg/kg/day will be used for
risk assessment.
For methomyl, EPA has decided that an MOE equal to or greater than
300 is considered protective. For calculating the MOE, an extra safety
factor of 3 will be used in addition to the usual 100 due to the lack
of acute and subchronic neurotoxicity studies (data gaps) as well as
the severity of effects (death in 1-3 days) seen at the 16 mg/kg/day
dose. Unlike thiodicarb, the two neurotoxicity studies on methomyl are
critical data gaps based on the fact that neurotoxicity has been
demonstrated in animals studies in two species (dog, rabbit) and by
both the oral and dermal routes of exposure. Because of the effects
observed, exposure to all population subgroups are of concern.
2. Short - and intermediate - term toxicity. While endpoints for
short- and intermediate- term dermal and inhalation exposures have been
identified they are not discussed here as they will not be used in this
tolerance assessment. Short- and intermediate-term risk analysis is
conducted when there may be primary dermal and inhalation exposure
which could result, for example, from residential pesticide
applications. Since there are no residential uses of thiodicarb EPA
believes that there is no exposure and therefore no short - and
intermediate - term risk (regardless of toxicity).
3. Chronic toxicity-- i. Thiodicarb. EPA has established the RfD
for thiodicarb at 0.03 milligrams/kilogram/day (mg/kg/day). This RfD is
based on a chronic rat toxicity study with a NOEL of 3.3 mg/kg/day for
males and 4.5 mg/kg/day for females. The LOEL was 12 mg/kg/day for
males and 15 mg/kg/day for females, based on the increased incidence of
extramedullary hemopoiesis in males and decreased RBC cholinesterase in
females. (MRID 43308201). An uncertainty factor (UF) of 100 was applied
to account for intraspecies variability and interspecies extrapolation.
ii. Methomyl. EPA has established the RfD for methomyl at 0.008
milligrams/kilogram/day (mg/kg/day). This RfD is based on a two-year
feeding study in dogs (MRID# 00007091) with a NOEL of 2.5 mg/kg/day.
The LOEL was 10 mg/kg/day based on histopathological effects in kidney.
An uncertainty factor (UF) of 100 was applied to account for both
inter-species extrapolation and intra-species variability. An extra
safety factor of 3 was applied in addition to the 100 due to the lack
of acute and subchronic neurotoxicity studies (data gaps).
4. Carcinogenicity-- i. Thiodicarb. The Health Effects Division
Carcinogenicity Peer Review Committee (CPRC) classified thiodicarb as
Group B2 - probable human carcinogen (document dated June 10, 1996).
The B2 classification was based on statistically significant
increases in hepatocellular adenomas, carcinomas, and combined adenoma/
carcinoma in both sexes of the CD-1 mouse at 1,000 mg/kg/day and
statistically significant increases in testicular interstitial cell
tumors in male Sprague-Dawley rats at 60 mg/kg/day.
The CPRC recommended that a non-linear methodology (MOE) be applied
for the estimation of human risk, with the point of departure set at
the 5 mg/kg/day dose, the lowest dose tested in the mouse
carcinogenicity study, based on the hepatocellular combined adenoma/
carcinoma in male mice.
The CPRC felt it was inappropriate to apply a linear low-dose
extrapolation to the animal data because the increased incidences of
tumors were statistically significant only at the highest dose in both
species; in the case of the mice, the highest tested dose (1,000 mg/kg/
day) is the limit dose for a carcinogenicity study and it may have been
excessive. In addition, there was no evidence of genotoxicity.
ii. Methomyl. The Health Effects Division Carcinogenicity Peer
Review Committee classified methomyl as Group E - the chemical is not
likely to be carcinogenic to humans via relevant routes of exposure
(document dated October 25, 1996).
C. Exposures and Risks
1. From food and feed uses. Tolerances have been established (40
CFR 180.407) for the combined residues of thiodicarb and its metabolite
methomyl, in or on a variety of raw agricultural commodities.
Thiodicarb has tolerances on sweet corn (2.0 ppm), cottonseed (0.4
ppm), and soybeans (0.2 ppm). Methomyl has tolerances on numerous crops
ranging from 0.1 to 10 ppm. There are no tolerances on meat, milk,
poultry, or eggs. Risk assessments were conducted by EPA to assess
dietary exposures and risks from thiodicarb as follows:
i. Acute exposure and risk. Acute dietary risk assessments are
performed for a food-use pesticide if a toxicological
[[Page 44589]]
study has indicated the possibility of an effect of concern occurring
as a result of a one day or single exposure.
To estimate acute dietary exposure for thiodicarb, the registrant
conducted Monte Carlo simulations for the overall U.S. population,
women 13 years and older, children 1 to 6 years of age, and infants.
These analyses included residues from field trial studies, consumption
data from the 1989 through 1992 USDA Continuing Survey of Food Intake
by Individuals (CSFII), and information on the percentages of the crop
treated.
Food consumption data from the USDA's CSFII conducted from 1989
through 1992 were used to estimate dietary exposure. The USDA provided
statistical weights that permitted the data from the various years of
the survey to be combined.
For the acute analysis, field trial residues were used for all
crops. In compliance with the EPA's guidance document, residue
distributions from field studies conducted at maximum label conditions
(e.g. maximum number of applications, maximum application rate, and
minimum preharvest intervals) were used for foods considered to be
single-serving commodities (e.g. cabbage, broccoli, lettuce); mean
field trial residues were used for blended/processed commodities (e.g.
cottonseed meal, soybean oil).
Processing factors were calculated for cottonseed meal, cottonseed
oil, and soybean oil. These factors were used in conjunction with the
mean field trial residues to estimate residue levels in the processed
commodities.
Residue values were adjusted for the percent of the crop estimated
to be treated with thiodicarb. These percentages were provided by the
Agency's Biological and Economic Analysis Division (BEAD). The maximum
percentage reported for a particular crop was used in the acute
exposure analyses. Percent crop treated information was not provided
for swiss chard, parsley, cress, and endive. The percent crop treated
for spinach was assumed for these crops.
Acute exposure estimates to thiodicarb were compared against the
developmental NOEL of 3 mg/kg/day from a rat developmental study in
which decreased pup body weight was observed. Because of the effects
observed, the population subgroup of concern is women of child-bearing
age. For the overall U.S. population, children 1 to 6 years of age, and
infants acute exposure estimates were compared against the maternal
NOEL of 10 mg/kg/day from a rat developmental study based on clinical
signs of tremors and inactivity.
The MOE is a measure of how close the high end exposure comes to
the NOEL (the highest dose at which no effects were observed in the
laboratory test), and is calculated as the ratio of the NOEL to the
exposure (NOEL/exposure = MOE). Generally, acute dietary MOEs greater
than 100 tend to cause no dietary concern to the Agency when results
are compared to animal-derived data. The MOEs for acute dietary
exposure were calculated using the estimates at the 99.9 percentile of
exposure for groups of concern. The acute exposure MOEs for the
application of thiodicarb are presented below in Table 1.
Table 1. Acute Exposure MOEs from the Application of Thiodicarb
------------------------------------------------------------------------
Group of Concern Exposure NOEL MOE
------------------------------------------------------------------------
U.S. Population............. 0.013792 10 mg/kg/day 218
Woman 13 years and older.... 0.013500 3 mg/kg/day 222
Children 1 to 6............. 0.022758 10 mg/kg/day 439
Infants..................... 0.010575 10 mg/kg/day 946
------------------------------------------------------------------------
The results of the acute exposure analyses indicate that there are
adequate MOEs (equal to or greater than 100) for the overall U.S.
population, the population subgroup of concern, women of child bearing
age, as well as for the, infants and children from the application of
thiodicarb.
ii. Chronic exposure and risk. For thiodicarb, a Dietary Risk
Evaluation System (DRES) chronic exposure analysis was performed using
tolerance level residues and BEAD percent crop treated information to
estimate the Anticipated Residue Contribution (ARC) for the general
population and 22 subgroups.
Using existing thiodicarb tolerances result in a TMRC which
represents 23%, 14%, and 36% of the RfD for the U.S. general
population, infants, and children (1 to 6 years old). A total of 22% of
the RfD is occupied by females (13+ years, nursing) which is the
highest subgroup. If more refined estimates of dietary exposure were
made (i.e., use of anticipated residues) lower chronic risks would be
estimated.
Even including the pending tolerances and the higher tolerance for
cottonseed, chronic dietary risk from food sources is not of concern.
For thiodicarb, the Cancer Peer Review Committee recommended that a
non-linear methodology (MOE) be applied for the estimation of human
cancer risk. The Cancer Peer Review Committee has determined that the
NOEL of 5 mg/kg/day be used as the point of departure for estimating
human risk. Cancer MOEs are estimated by dividing the NOEL of 5 mg/kg/
day, by the chronic exposure. The assessment was conducted for the
Total U.S. Population only.
Exposure = ARC = 0.007 mg/kg/day
MOE = NOEL Exposure = 5 mg/kg/day 0.007 mg/kg/day
= 714
The MOE of 714 assumes all residues to be at tolerance level.
Percent crop treated information was utilized.
2. From drinking water. Thiodicarb breaks down rapidly in the
environment to methomyl. Methomyl, the major degradate of thiodicarb,
is very mobile and persists in the field for a time sufficient (field
dissipation half life = 18 days) to leach into groundwater. This
tendency is enhanced when soils are permeable and the water table is
high.
Since thiodicarb breaks down rapidly to methomyl, EPA has estimated
the exposure and risk associated with the highest methomyl residues
detected in ground water monitoring studies and with the PRZM/EXAMS
model numbers for surface water.
The following assumptions have been made to estimate exposure;
water consumption is defined as all water obtained from the household
tap that is consumed either directly as a beverage or used to prepare
foods and beverages. For the adult male exposure calculation, the
average adult body weight is assumed to be 70 kg, and it is assumed
that the average adult consumes 2 liters of water (l)/day. For
children's exposure, the average body weight is assumed to be 10 kg and
the average water consumption is assumed to be 1 liter per day.
The other assumption inherent in this calculation is that water
from the same source containing the same contaminant level is consumed
throughout a 70-year lifetime. The second of these assumptions is
extremely conservative, since most members of the U.S. population move
at some time during their lifetime and do not live in the same area or
drink from the same water source for a 70-year lifetime.
Exposure is calculated using the following formula for
adults(males):
Exposure = (chemical concentration in g/L in ground and/or
surface water) x (10-3 mg/g) (70 kg body
weight) x (2L water consumed/day)
For children (1 to 6 years old), the exposure would be calculated
using the following formula:
[[Page 44590]]
Exposure = (chemical concentration in g/L in ground and/or
surface water) x (10-3 mg/g) (10 kg body
weight) x (1L water consumed/day)
i. Acute exposure and risk. Thiodicarb breaks down rapidly in the
environment to methomyl and methomyl is the pesticide that was
monitored in ground water and surface water studies. The methomyl acute
dietary endpoint is used for the acute dietary risk from water and is
based on the maternal toxicity NOEL of 6 mg/kg/ day from the rabbit
developmental toxicity study. For calculating the MOE, an extra safety
factor of 3 will be used in addition to the 100 (MOE = 300) due to the
lack of acute and subchronic neurotoxicity studies as well as the
severity of effects seen in the rabbit developmental toxicity study.
The EPA estimate for methomyl in ground water to be used in the
acute exposure analyses is 20 ppb and is based on a small-scale
prospective ground water study performed by DuPont. The EFED-supplied
estimate for methomyl in surface water is 30 ppb which is based on a
worst-case PRZM/EXAMS run showing a concentration of 151 ppb in an
agricultural farm pond and a DuPont ecological monitoring study showing
a minimum 5-8 fold dilution factor. The use of the 5-fold dilution
factor in estimating the concentration in surface water thus accounts
for the high end of the possible range.
a. Adult male acute exposure.
Methomyl exposure (highest concentration detected in ground water)
= (20 g/L) x (10-3 mg/g) (70 kg
body weight) x (2L day) = 5.7 x 10-4 mg/kg/day.
Methomyl exposure (highest concentration modeled in surface water)
= (30 g/L) x (10-3 mg/g) (70 kg
body weight) x (2L day) = 8.57 x 10-4 mg/kg/day.
The highest exposure number will be used for acute water risk
assessment for g/L) x (10-3 mg/g)
(70 kg body weight) x (2L day) = 8.57 x 10-4 mg/kg/day.
b. Children's (1 to 6 years old) acute exposure.
Methomyl exposure (highest concentration detected in ground water)
= (20 g/L) x (10-3 mg/g) (10 kg
body weight) x (1L day) = 2.0 x 10-3mg/kg/day.
Methomyl exposure (highest concentration modeled in surface water)
= (30 g/L) x (10-3 mg/g) (10 kg
body weight) x (1L day) = 3.0 x 10-3 mg/kg/day.
The highest exposure number will be used for acute water risk
assessment for g/L) x (10-3 mg/g)
(10 kg body weight) x (1L day) = 3.0 x 10-3 mg/kg/day.
c. Acute risk-water.
NOEL//Exposure = MOE
Adult (male) MOE = 6 mg/kg/day acute water exposure (8.57
x 10-4mg/kg/day) = 7,001
Children's MOE = 6 mg/kg/day acute water exposure(3 x
10-3 mg/kg/day) =2,000
ii. Chronic exposure and risk. The chronic estimated environmental
concentration for methomyl is 26 ppb for surface water and 2 ppb for
ground water.
a. Adult male chronic exposure.
Methomyl exposure (average concentration detected in ground water)
= (2 g/L) x (10-3 mg/g) (70 kg
body weight) x (2L day) = 5.7 x 10-5 mg/kg/day.
Methomyl exposure (average concentration detected in surface water)
= (26 g/L) x (10-3 mg/g) (70 kg
body weight) x (2L day) = 7.4 x 10-4 mg/kg/day.
The highest exposure number will be used for chronic water risk
assessment = 7.4 x 10-4.
b. Children's(1 to 6 years old) chronic exposure.
Methomyl exposure (average concentration detected in ground water)
= (2 g/L) x (10-3 mg/g) (10 kg
body weight) x (1L day) = 2.0 x 10-4 mg/kg/day.
Methomyl exposure (average concentration modeled in surface water)
= (26 g/L) x (10-3 mg/g) (10 kg
body weight) x (1L day) = 2.6 x 10-3 mg/kg/day.
The highest exposure number will be used for acute water risk
assessment for children = 2.6 x 10-3.
c. Chronic Risk- Water. The chronic dietary endpoint, the RfD, is
0.008 mg/kg/day for methomyl, and is used to calculate the chronic
dietary risk. The RfD was established based on a 2-year dog feeding/
carcinogenicity study with a NOEL of 2.5 mg/kg/day and an uncertainty
factor of 100 to account for both inter-species extrapolation and
intra-species variability. An additional uncertainty factor of 3 was
applied to account for the lack of acute and subchronic neurotoxicity
studies.
The chronic dietary risk from ground and surface water is expressed
as a percentage of the RfD through the following formula:
chronic water exposure mg/kg/day RfD mg/kg/day x 100 = %
RfD
%RfD Adult (male) = 7.4 x 10-4 0.008 mg/kg/day
x 100 =9%RfD
%RfD Children(1 to 6 years) = 2.6 x 10-3 0.008
mg/kg/day x 100 =33%RfD
3. From non-dietary exposure. Thiodicarb is not currently
registered for any residential uses. Since there are no residential
uses of thiodicarb, EPA does not believe that there will be any risk
associated with non-dietary exposure.
4. Cumulative exposure to substances with common mechanism of
toxicity. Section 408(b)(2)(D)(v) requires that, when considering
whether to establish, modify, or revoke a tolerance, the Agency
consider ``available information'' concerning the cumulative effects of
a particular pesticide's residues and ``other substances that have a
common mechanism of toxicity.'' The Agency believes that ``available
information'' in this context might include not only toxicity,
chemistry, and exposure data, but also scientific policies and
methodologies for understanding common mechanisms of toxicity and
conducting cumulative risk assessments. For most pesticides, although
the Agency has some information in its files that may turn out to be
helpful in eventually determining whether a pesticide shares a common
mechanism of toxicity with any other substances, EPA does not at this
time have the methodologies to resolve the complex scientific issues
concerning common mechanism of toxicity in a meaningful way. EPA has
begun a pilot process to study this issue further through the
examination of particular classes of pesticides. The Agency hopes that
the results of this pilot process will increase the Agency's scientific
understanding of this question such that EPA will be able to develop
and apply scientific principles for better determining which chemicals
have a common mechanism of toxicity and evaluating the cumulative
effects of such chemicals. The Agency anticipates, however, that even
as its understanding of the science of common mechanisms increases,
decisions on specific classes of chemicals will be heavily dependent on
chemical specific data, much of which may not be presently available.
Although at present the Agency does not know how to apply the
information in its files concerning common mechanism issues to most
risk assessments, there are pesticides as to which the common mechanism
issues can be resolved. These pesticides include pesticides that are
toxicologically dissimilar to existing chemical substances (in which
case the Agency can conclude that it is unlikely that a pesticide
shares a common mechanism of activity with other substances) and
pesticides that produce a common toxic metabolite (in which case common
mechanism of activity will be assumed).
[[Page 44591]]
EPA does not have, at this time, available data to determine
whether thiodicarb has a common mechanism of toxicity with other
substances or how to include this pesticide in a cumulative risk
assessment. For the purposes of this tolerance action, therefore, EPA
has not assumed that thiodicarb has a common mechanism of toxicity with
other substances. However, the Agency has determined that thiodicarb
has a metabolite which is a registered pesticide, methomyl. Therefore,
for this tolerance determination, methomyl residues resulting from
applications of both thiodicarb and methomyl will be considered in a
cumulative risk assessment and compared to appropriate toxicological
endpoints for methomyl.
D. Aggregate Risks and Determination of Safety for U.S. Population
In examining aggregate exposure, FQPA directs EPA to take into
account available information concerning exposures from pesticide
residues in food and other exposures or which there is reliable
information. These other exposures include drinking water and non-
occupational exposures, e.g., to pesticides used in and around the
home. Risk assessments for aggregate exposure consider both short-term
and long-term (chronic) exposure scenarios considering the toxic
effects which would likely be seen for each exposure duration.
Thiodicarb is a food use chemical. There are no residential (non-
occupational) uses of thiodicarb; therefore, the considerations for
aggregate exposure are those from food and drinking water.
1. Acute risk. The registrant provided an acute dietary Monte Carlo
distributional risk assessment which combined residues of methomyl from
the application of thiodicarb and residues of methomyl from the
application of methomyl . The methomyl acute dietary NOEL of 6 mg/kg/
day was used to calculate the MOE.
Since methomyl, rather than thiodicarb, per se is expected in
ground and surface water as a result of thiodicarb applications, an
acute aggregate risk from thiodicarb residues includes only risks from
food. This assessment is discussed in the previous section under risk
characterization for thiodicarb.
Acute exposures to methomyl residues from all sources (food and
water, from thiodicarb and methomyl applications) will be aggregated
and compared to the methomyl acute dietary NOEL. Using exposure
estimates provided by the registrant, EPA estimated MOEs for various
U.S. subpopulations based on acute effects and 24-hour intervals using
a NOEL = 6 mg/kg BW/day. This includes residues from methomyl in food
as a result of application of thiodicarb, from methomyl in food as a
result of application of methomyl, and from methomyl in water. See
Table 2.
Table 2. EPA-estimated Margins of Exposure (MOEs)
----------------------------------------------------------------------------------------------------------------
Food Food and Water Combined
-----------------------------------------------------------------------------
24 hour interval 24 hour interval
Population Group percentile -----------------------------------------------------------------------------
mg/kg BW/
day MOE mg/kg BW/day MOE
----------------------------------------------------------------------------------------------------------------
U.S. Population
95th.............................. 0.000349 017192 0.001206 04975
99th.............................. 0.001099 5460 0.001956 3067
99.9th............................ 0.006577 0912 0.007434 807
Infants
95th.............................. 0.000215 27907 0.003215 1866
99th.............................. 0.000874 6865 0.003874 1549
99.9th........................... 0.007940 756 0.01094 548
Children 1-6 years
95th.............................. 0.000482 12448 0.003482 1723
99th.............................. 0.002108 2846 0.005108 1175
99.9th............................ 0.014396 417 0.017396 345
----------------------------------------------------------------------------------------------------------------
Overall, these estimates are likely to be conservative estimates of
the MOE. For example, it assumes that residues, when present, are
present as a result of application at the maximum permitted level and
observance of the minimum PHI. No reduction as a result of transport
time from farm gate to consumer is assumed to occur. Also, no further
reduction of residues through washing, peeling, or cooking at the
producer or consumer level is assumed to occur. EPA concludes that
sufficient margins of exposure exist at various high-end percentile
exposure levels of interest (e.g., 95th, 99th, and 99.9th percentile
values) and that there are no acute concerns associated with potential
residues of methomyl (resulting from use of either thiodicarb or
methomyl) in foods or drinking water.
2. Chronic risk. Chronic exposures to methomyl residues from all
sources (food and water, from thiodicarb and methomyl applications)
will be aggregated and compared to the methomyl reference dose.
Therefore aggregate chronic risk for thiodicarb residues includes only
risks from food and is shown in the previous section.
Results of the chronic exposure analysis show that no single
subpopulation exceeded 7% of the RfD. The two most significantly
exposed subpopulations are non-nursing infants (<1 year="" old)="" and="" all="" infants="" with="" 6.5%="" and="" 5.2%="" of="" the="" rfd="" occupied,="" respectively.="" for="" the="" overall="" u.s.="" population,="" only="" 1.9%="" of="" the="" rfd="" was="" occupied).="" the="" aggregated="" chronic="" exposure="" from="" methomyl="" in="" food="" as="" a="" result="" of="" application="" of="" thiodicarb,="" from="" methomyl="" in="" food="" as="" a="" result="" of="" application="" of="" methomyl,="" and="" from="" methomyl="" in="" water="" is="" shown="" in="" table="" 3="" below.="" table="" 3.="" chronic="" aggregate="" exposure="" ----------------------------------------------------------------------------------------------------------------="" population="" subgroup="" dietary="">a Water %RfD Totalb
----------------------------------------------------------------------------------------------------------------
U. S. General........................ 1.9 9 11
Children (1 to 6).................... 2.7 33 36
[[Page 44592]]
Infants.............................. 6.5 33 40
----------------------------------------------------------------------------------------------------------------
a Dietary % RfD includes methomyl residues from application of thiodicarb and methomyl.
b Although the Novigen chronic analyses incorporated exposure to both food and water, water concentrations were
assumed in their analyses to be 4 ppb. The Agency believes that 26 ppb is a more appropriate estimate.
Therefore, chronic water exposure were calculated independently by the Agency using the 26 ppb estimate. The
total exposure reflected here incorporates both of these estimates and therefore slightly overestimates the
chronic risk.
3. Short- and intermediate-term risk. Short- and intermediate-term
risk analysis is conducted when there may be primary dermal and
inhalation exposure which could result, for example, from residential
pesticide applications. Since there are no residential uses of
thiodicarb, EPA does not believe that there will be any exposure or
risk associated with non-occupational, non-water uses.
E. Aggregate Cancer Risk for U.S. Population
Thiodicarb is a Group B2 carcinogen (probable carcinogenic
effects); methomyl is a Group E carcinogen (no carcinogenic effects
likely). Aggregated cancer risks are equal to the risks from
thiodicarb; there is no cancer risk added from methomyl.
No aggregate cancer risk assessment is required because methomyl is
not a carcinogen and methomyl, rather than thiodicarb, per se, is
expected in ground and surface water.
F. Aggregate Risks and Determination of Safety for Infants and Children
1. Safety factor for infants and children-- i. Thiodicarb-- a. In
general. In assessing the potential for additional sensitivity of
infants and children to residues of thiodicarb, EPA considered data
from developmental toxicity studies in the rat, mice, and rabbit and a
two-generation reproduction study in the rat. The developmental
toxicity studies are designed to evaluate adverse effects on the
developing organism resulting from pesticide exposure to the mother
during prenatal development. Reproduction studies provide information
relating to effects from exposure to the pesticide on the reproductive
capability of mating animals and data on systemic toxicity.
FFDCA section 408 provides that EPA shall apply an additional
tenfold margin of safety for infants and children in the case of
threshold effects to account for pre-and post-natal toxicity and the
completeness of the database unless EPA determines that a different
margin of safety will be safe for infants and children. Margins of
safety are incorporated into EPA risk assessments either directly
through use of a MOE analysis or through using uncertainty (safety)
factors in calculating a dose level that poses no appreciable risk to
humans. EPA believes that reliable data support using the standard MOE
and uncertainty factor (usually 100 for combined inter- and intra-
species variability)) and not the additional tenfold MOE/uncertainty
factor when EPA has a complete data base under existing guidelines and
when the severity of the effect in infants or children or the potency
or unusual toxic properties of a compound do not raise concerns
regarding the adequacy of the standard MOE/safety factor.
b. Developmental toxicity studies. In a rat developmental toxicity
study, pregnant Charles River CD COBS rats were administered thiodicarb
via gavage on gestation days 6-19 at dose levels of 0 (vehicle 0.5%
methocel), 10, 20, and 30 mg thiodicarb/kg body weight/day. In another
rat developmental toxicity study, pregnant Fisher 344 rats were dosed
via the diet on (1) gestation days 6 to 15 or (2) gestation days 0-20
at dose levels of 0.5, 1.0, 3.0, and 100 mg thiodicarb (>99%)/kg body
weight/day. When these two studies are considered together, the
maternal toxicity NOEL is 10 mg/kg/day, and the maternal toxicity LOEL
is 20 mg/kg/day, based on clinical signs (tremors, inactivity). The
developmental toxicity NOEL is 3 mg/kg/day, and the LOEL is 10 mg/kg/
day, based on decreased fetal body weights and increased incidence of
litters and fetuses with developmental variations which included
unossification of sternebrae #5 and/or #6 and other sternebrae (MRIDs
00043739, 00043740, 00043741, 00053254, 00053255, 00053256).
In a developmental toxicity study, artificially-inseminated New
Zealand white rabbits were administered thiodicarb via gavage on
gestation days 6 through 19 at dose levels of 0 (vehicle, 0.5% aqueous
methylcellulose), 5, 20, and 40 mg/kg/day. The maternal toxicity NOEL
was 20 mg/kg/day, and the maternal toxicity LOEL was 40 mg/kg/day,
based on reduced body-weight gain and food consumption. The
developmental toxicity NOEL was 40 mg/kg/day, the highest dose tested
(MRIDs 00159814, 40280001).
In a developmental toxicity study, Charles River CD-1 mice were
administered thiodicarb on gestation days 6 through 16 via gavage at
dose levels of 0 (vehicle 0.5% methocel), 50, 100, and 200 mg
Thiodicarb/kg body weight/day. The maternal toxicity NOEL was 100 mg/
kg/day, and the maternal toxicity LOEL was 200 mg/kg/day, based on
increased mortality. The developmental toxicity NOEL was 200 mg/kg/day,
the highest dose tested (MRIDs 00043742, 00043743, 00053257, 00053258).
c. Reproductive toxicity study. In a two-generation reproduction
study, Crl:CD BR/VAF/Plus rats were fed doses of
0, 5, 15, and 45 mg/kg/day of thiodicarb. The reproductive/
developmental toxicity NOEL is 5 mg/kg/day, and the reproductive/
developmental toxicity LOEL is 15 mg/kg/day, based on decreased fetal
body weight and viability. The systemic NOEL is 5 mg/kg/day and the
systemic LOEL is 15 mg/kg/day, based on decreased body weight/gain and
food consumption in both sexes (MRIDs 42381301, 42381302, 42735101).
d. Pre- and post-natal sensitivity. There is no evidence of
additional sensitivity to offspring following pre- and/or postnatal
exposure to thiodicarb. In the two-generation reproduction study in
rats, reproductive/developmental effects in pups (decreased body weight
and viability) were observed only at dietary levels which were toxic in
the parental animals, as evidenced by decreased body weight and food
consumption. In the prenatal developmental toxicity studies in mice and
rabbits, no developmental toxicity was observed, even at maternally
toxic doses. In rats, two prenatal developmental toxicity studies were
conducted, and based on the combined results of these studies, the
developmental NOEL of 3 mg/kg/day was determined. This developmental
NOEL was based upon decreased fetal body weight and increased incidence
of delayed ossification in the sternebrae and was lower than the
maternal NOEL of 10 mg/kg/day, which was based upon clinical signs of
tremors and inactivity. Although these results could indicate an
additional sensitivity of offspring to prenatal exposure to thiodicarb,
the results are derived from two separate studies, using two different
strains of rat (Sprague-Dawley and Wistar) which could alter the fetal
response to prenatal exposure. Additionally, the developmental NOEL was
identified in the second prenatal study, while all other NOELs and
LOELs were identified in the first study. The dose level at which the
developmental NOEL was established is, in many ways, an artifact of
dose selection, since the next higher
[[Page 44593]]
dose was 33 times greater than that which demonstrated no fetal
effects. If a wide spectrum of dose levels had been selected for
testing in this strain of rat, it is very possible that no indication
of additional fetal sensitivity would have been observed (as they were
not in the other two studies).
e. Conclusion. Although there is a data gap (acute neurotoxicity
study), EPA has determined that this is simply a confirmatory study.
Other than this study, the database is complete. While tremors and
inactivity were observed in one developmental study, other instances of
neurotoxic behavior have not been observed in the remaining studies.
There is no evidence of increased sensitivity to infants or children.
FQPA directs the Agency to utilize an additional tenfold margin of
safety to protect the health of infants and children unless the Agency
concludes based on reliable data that a different margin will be safe
for infants and children. Based on the considerations outlined above,
the Agency has concluded that there is reliable data demonstrating that
an uncertainty factor of 100 is safe for infants and children and that
an additional 10x margin of safety is not necessary.
ii. Methomyl-- a. In general. In assessing the potential for
additional sensitivity of infants and children to residues of methomyl,
EPA considered data from developmental toxicity studies in the rat,
mice, and rabbit and a two-generation reproduction study in the rat.
b. Developmental toxicity studies. Methomyl (99 - 100%) was
administered to 25 presumed pregnant Charles River-CD (ChR-CD) rats/
group in the diet at concentrations of 0, 50, 100 and 400 ppm (0, 4.9,
9.4 and 33.9 mg/kg/day) on gestation days 6 through 16. The data did
not reveal any apparent developmental toxicity. The NOEL for maternal
toxicity is 100 ppm (9.4 mg/kg/day) and the LOEL is 400 ppm (33.9 mg/
kg/day) based on decreased body weight gain and food consumption during
gestation. The NOEL for developmental toxicity is 400 ppm (33.9 mg/kg/
day) (MRID 00008621).
Methomyl (98.7%) was administered via stomach tube to 20 presumed
pregnant New Zealand white (DLI:NZW) rabbits per group (19 in the high-
dose group) at dosages of 0, 2, 6 and 16 mg/kg/day on gestation days 7
through 19. Clinical signs indicated neurotoxic effects in high-dose
rabbits. There was no evidence of developmental toxicity in this study.
The NOEL for developmental toxicity is 16 mg/kg/day. The NOEL for
maternal toxicity is 6 mg/kg/day and the LOEL is 16 mg/kg/day based on
mortalities and clinical signs (MRID 00131257).
c. Reproductive toxicity study. Sprague-Dawley rats in the
F0 parental generation were fed methomyl at dose levels of
0, 75, 600 or 1200 ppm (0, 3.75, 30, or 60 mg/kg/day, respectively,
based on the standard conversion ratio). The F1 offspring
were treated at the same dosages. There was a dose-related increase in
clinical signs involving the nervous system during the first few weeks
of the study and the incidence of alopecia was increased in the 600 and
1,200 ppm group animals. The NOEL for systemic toxicity is 75 ppm (3.75
mg/kg/day) and the LOEL is 600 ppm (30 mg/kg/day) based on decreased
body weight and food consumption and altered hematology parameters. The
NOEL for reproductive toxicity is 75 ppm (3.75 mg/kg/day) and the LOEL
is 600 ppm (30 mg/kg/day) based on decreases in both the mean number of
live pups and mean body weights of offspring (MRID 43250701).
d. Pre- and post-natal sensitivity. In the rat developmental
toxicity study the maternal NOEL is less than the developmental NOEL.
In the rabbit developmental toxicity study there was no evidence of
developmental toxicity. In the reproductive toxicity study the systemic
NOEL is equal to the reproductive NOEL.
e. Conclusion. For calculating the MOE, an extra safety factor of 3
will be used in addition to the usual 100 due to the lack of acute and
subchronic neurotoxicity studies (data gaps) as well as the severity of
effects (death in 1-3 days) seen at the 16 mg/kg/day dose. Unlike
thiodicarb, the two neurotoxicity studies on methomyl are critical data
gaps based on the fact that neurotoxicity has been demonstrated in
animals studies in two species (dog, rabbit) and by both the oral and
dermal routes of exposure.
There is no evidence of increased sensitivity to infants or
children. FQPA directs the Agency to utilize an additional tenfold
margin of safety to protect the health of infants and children unless
the Agency concludes based on reliable data that a different margin
will be safe for infants and children. Based on the considerations
outlined above, the Agency has concluded that there is reliable data
demonstrating that an uncertainty factor of 300 is protective of
infants and children and that an additional margin of safety is not
necessary. The 300 uncertainty factor is composed of the interspecies
uncertainty factor of 10, the intraspecies uncertainty factor of 10,
and an additional factor of 3 to compensate for the lack of acute and
subchronic neurotoxicity studies as well as the severity of effects
(death in 1-3 days) seen at the 16 mg/kg/day dose.
2. Acute risk. For thiodicarb, to estimate acute dietary exposure,
the registrant conducted Monte Carlo simulations for children (1 to 6
years) and infants. Acute dietary exposure estimates at the 99.9
percentile of exposure for children (1 to 6 years) and infants resulted
in MOEs of 439 and 946, respectively. The results of the acute exposure
analysis indicate that there are adequate Margins of Exposure (MOEs)
greater than 100 for infants and children for thiodicarb.
For methomyl, for acute aggregate risk (from methomyl in food as a
result of application of thiodicarb, from methomyl in food as a result
of application of methomyl, and from methomyl in water), the dietary
exposure number (6.57 x 10-3 ) from a Novigen Monte Carlo
analysis and the acute water exposure number (8.57 x 10-4)
were combined and resulted in an aggregate exposure of 7.43 x
10-3. When compared against the methomyl NOEL of 6 mg/kg/day
the acute aggregate MOEs for children (1-6 years) and infants were 345
and 548, respectively. The results of the acute aggregate exposure
analysis indicate that there are adequate MOEs greater than 300 for
infants and children for methomyl.
3. Chronic risk. For methomyl, for chronic aggregate risk,
exposures (from methomyl in food as a result of application of
thiodicarb, from methomyl in food as a result of application of
methomyl, and from methomyl in water) were combined and compared to the
methomyl reference dose. The two most significantly exposed
subpopulations are non-nursing infants (<1 year="" old)="" and="" children="" (1-6="" years="" old)="" with="" 40%="" and="" 36%="" of="" the="" rfd="" occupied,="" respectively.="" a="" thiodicarb,="" chronic="" dietary="" risk="" assessment="" was="" conducted="" using="" tolerance="" level="" residues="" and="" bead="" percent="" crop="" treated="" information.="" the="" chronic="" analysis="" indicates="" that="" exposure="" from="" the="" existing="" permanent="" and="" time-limited="" tolerances="" for="" children(1="" to="" 6="" years="" old)="" and="" infants,="" 36%="" and="" 14%,="" respectively,="" of="" the="" rfd="" would="" be="" consumed.="" chronic="" dietary="" risk="" considering="" consumption="" of="" thiodicarb="" from="" food="" sources="" is="" not="" of="" concern.="" 4.="" short-="" or="" intermediate-term="" risk.="" short-="" and="" intermediate-term="" risk="" analysis="" is="" conducted="" when="" there="" may="" be="" primary="" dermal="" and="" inhalation="" exposure="" which="" could="" result,="" for="" example,="" from="" residential="" pesticide="" applications.="" since="" there="" are="" no="" residential="" uses="" of="" thiodicarb,="" epa="" does="" [[page="" 44594]]="" not="" believe="" that="" there="" will="" be="" any="" exposure="" or="" risk="" for="" infants="" or="" children="" associated="" with="" non-occupational,="" non-water="" uses.="" iii.="" other="" considerations="" a.="" metabolism="" in="" plants="" and="" animals="" the="" qualitative="" nature="" of="" the="" residue="" in="" plants="" is="" adequately="" understood="" based="" on="" soybean,="" tomato,="" cotton,="" sweet="" corn="" and="" peanut="" metabolism="" studies.="" the="" residues="" to="" be="" regulated="" in="" plants="" are="" thiodicarb="" and="" its="" metabolite="" methomyl.="" the="" qualitative="" nature="" of="" the="" residue="" in="" animals="" is="" adequately="" understood="" based="" upon="" acceptable="" ruminant="" and="" poultry="" metabolism="" studies.="" the="" residues="" to="" be="" regulated="" in="" livestock="" are="" thiodicarb="" and="" its="" metabolite="" methomyl.="" b.="" analytical="" enforcement="" methodology="" adequate="" analytical="" methodology="" is="" available="" for="" enforcement="" of="" tolerances="" of="" thiodicarb.="" method="" i="" in="" the="" pesticide="" analytical="" manual="" (pam),="" vol.="" ii,="" is="" a="" glc/sulfur="" specific="" flame="" photometric="" detector="" (fpd-s)="" method="" that="" has="" undergone="" a="" successful="" epa="" method="" validation.="" the="" reported="" limit="" of="" detection="" is="" 0.02="" ppm="" for="" plant="" commodities.="" an="" enforcement="" analytical="" method="" for="" livestock="" commodities="" is="" not="" necessary="" since="" there="" are="" no="" significant="" animal="" feed="" items="" associated="" with="" the="" subject="" crops.="" c.="" magnitude="" of="" residues="" residues="" of="" thiodicarb="" or="" its="" metabolites="" are="" not="" expected="" to="" exceed="" 35="" ppm="" in/on="" leafy="" vegetables="" (except="" brassicaa="" vegetables)="" and="" 7="" ppm="" in/on="" broccoli,="" cabbage,="" and="" cauliflower="" as="" a="" result="" of="" this="" use.="" d.="" international="" residue="" limits="" there="" are="" no="" codex,="" canadian,="" or="" mexican="" tolerances="" for="" thiodicarb="" in/on="" leafy="" vegetables,="" broccoli,="" cabbage="" or="" cauliflower.="" therefore,="" there="" are="" no="" questions="" with="" respect="" to="" compatibility="" of="" u.s.="" tolerances="" with="" codex="" mrls.="" iv.="" conclusion="" therefore,="" the="" tolerance="" is="" established="" for="" combined="" residues="" of="" thiodicarb="" and="" its="" metabolite="" methomyl="" in="" broccoli="" at="" 7="" ppm,="" cabbage="" at="" 7="" ppm,="" cauliflower="" at="" 7="" ppm,="" and="" leafy="" vegetables="" (except="" brassica="" vegetables)="" at="" 35="" ppm.="" v.="" objections="" and="" hearing="" requests="" the="" new="" ffdca="" section="" 408(g)="" provides="" essentially="" the="" same="" process="" for="" persons="" to="" ``object''="" to="" a="" tolerance="" regulation="" issued="" by="" epa="" under="" new="" section="" 408(e)="" and="" (l)(6)="" as="" was="" provided="" in="" the="" old="" section="" 408="" and="" in="" section="" 409.="" however,="" the="" period="" for="" filing="" objections="" is="" 60="" days,="" rather="" than="" 30="" days.="" epa="" currently="" has="" procedural="" regulations="" which="" govern="" the="" submission="" of="" objections="" and="" hearing="" requests.="" these="" regulations="" will="" require="" some="" modification="" to="" reflect="" the="" new="" law.="" however,="" until="" those="" modifications="" can="" be="" made,="" epa="" will="" continue="" to="" use="" those="" procedural="" regulations="" with="" appropriate="" adjustments="" to="" reflect="" the="" new="" law.="" any="" person="" may,="" by="" october="" 22,="" 1997,="" file="" written="" objections="" to="" any="" aspect="" of="" this="" regulation="" and="" may="" also="" request="" a="" hearing="" on="" those="" objections.="" objections="" and="" hearing="" requests="" must="" be="" filed="" with="" the="" hearing="" clerk,="" at="" the="" address="" given="" above="" (40="" cfr="" 178.20).="" a="" copy="" of="" the="" objections="" and/or="" hearing="" requests="" filed="" with="" the="" hearing="" clerk="" should="" be="" submitted="" to="" the="" opp="" docket="" for="" this="" rulemaking.="" the="" objections="" submitted="" must="" specify="" the="" provisions="" of="" the="" regulation="" deemed="" objectionable="" and="" the="" grounds="" for="" the="" objections="" (40="" cfr="" 178.25).="" each="" objection="" must="" be="" accompanied="" by="" the="" fee="" prescribed="" by="" 40="" cfr="" 180.33(i).="" if="" a="" hearing="" is="" requested,="" the="" objections="" must="" include="" a="" statement="" of="" the="" factual="" issues="" on="" which="" a="" hearing="" is="" requested,="" the="" requestor's="" contentions="" on="" such="" issues,="" and="" a="" summary="" of="" any="" evidence="" relied="" upon="" by="" the="" requestor="" (40="" cfr="" 178.27).="" a="" request="" for="" a="" hearing="" will="" be="" granted="" if="" the="" administrator="" determines="" that="" the="" material="" submitted="" shows="" the="" following:="" there="" is="" genuine="" and="" substantial="" issue="" of="" fact;="" there="" is="" a="" reasonable="" possibility="" that="" available="" evidence="" identified="" by="" the="" requestor="" would,="" if="" established,="" resolve="" one="" or="" more="" of="" such="" issues="" in="" favor="" of="" the="" requestor,="" taking="" into="" account="" uncontested="" claims="" or="" facts="" to="" the="" contrary;="" and="" resolution="" of="" the="" factual="" issues="" in="" the="" manner="" sought="" by="" the="" requestor="" would="" be="" adequate="" to="" justify="" the="" action="" requested="" (40="" cfr="" 178.32).="" information="" submitted="" in="" connection="" with="" an="" objection="" or="" hearing="" request="" may="" be="" claimed="" confidential="" by="" marking="" any="" part="" or="" all="" of="" that="" information="" as="" confidential="" business="" information="" (cbi).="" information="" so="" marked="" will="" not="" be="" disclosed="" except="" in="" accordance="" with="" procedures="" set="" forth="" in="" 40="" cfr="" part="" 2.="" a="" copy="" of="" the="" information="" that="" does="" not="" contain="" cbi="" must="" be="" submitted="" for="" inclusion="" in="" the="" public="" record.="" information="" not="" marked="" confidential="" may="" be="" disclosed="" publicly="" by="" epa="" without="" prior="" notice.="" vi.="" public="" docket="" epa="" has="" established="" a="" record="" for="" this="" rulemaking="" under="" docket="" control="" number="" [opp-300541]="" (including="" any="" comments="" and="" data="" submitted="" electronically).="" a="" public="" version="" of="" this="" record,="" including="" printed,="" paper="" versions="" of="" electronic="" comments,="" which="" does="" not="" include="" any="" information="" claimed="" as="" cbi,="" is="" available="" for="" inspection="" from="" 8:30="" a.m.="" to="" 4="" p.m.,="" monday="" through="" friday,="" excluding="" legal="" holidays.="" the="" public="" record="" is="" located="" in="" room="" 1132="" of="" the="" public="" information="" and="" records="" integrity="" branch,="" information="" resources="" and="" services="" division="" (7506c),="" office="" of="" pesticide="" programs,="" environmental="" protection="" agency,="" crystal="" mall="" #2,="" 1921="" jefferson="" davis="" hwy.,="" arlington,="" va.="" electronic="" comments="" may="" be="" sent="" directly="" to="" epa="" at:="">opp-docket@epamail.epa.gov.
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption.
The official record for this rulemaking, as well as the public
version, as described above will be kept in paper form. Accordingly,
EPA will transfer any copies of objections and hearing requests
received electronically into printed, paper form as they are received
and will place the paper copies in the official rulemaking record which
will also include all comments submitted directly in writing. The
official rulemaking record is the paper record maintained at the
Virginia address in ``ADDRESSES'' at the beginning of this document.
VII. Regulatory Assessment Requirements
This final rule establishes a tolerance 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). 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., or impose any enforceable
duty or contain any unfunded mandate as described under Title II of the
Unfunded Mandates Reform Act of 1995 (UMRA) (Pub. L. 104-4). Nor does
it require any prior consultation as specified by Executive Order
12875, entitled Enhancing the Intergovernmental Partnership (58 FR
58093, October 28, 1993), or special considerations as required by
Executive Order 12898, entitled Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations (59 FR 7629, February 16, 1994), or require OMB review in
[[Page 44595]]
accordance with Executive Order 13045, entitled Protection of Children
from Environmental Health Risks and Safety Risks (62 FR 19885, April
23, 1997).
In addition, since these 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. Nevertheless, the Agency has
previously assessed whether establishing tolerances, exemptions from
tolerances, raising tolerance levels or expanding exemptions might
adversely impact small entities and concluded, as a generic matter,
that there is no adverse economic impact. The factual basis for the
Agency's generic certification for tolerance actions was published on
May 4, 1981 (46 FR 24950) and was provided to the Chief Counsel for
Advocacy of the Small Business Administration.
VIII. Submission to Congress and the General Accounting Office
Under 5 U.S.C. 801(a)(1)(A), as added by the Small Business
Regulatory Enforcement Fairness Act of 1996, the Agency has submitted 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 General Accounting Office prior to publication of this rule in
today's Federal Register. This is not a ``major rule'' as defined by 5
U.S.C. 804(2).
List of Subjects in 40 CFR Parts 180 and 186
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Animal feeds, Pesticides and pests, Reporting
and recordkeeping requirements.
Dated: August 15, 1997.
Stephen L. Johnson,
Acting Director, Registration Division, Office of Pesticide Programs.
Therefore, 40 CFR chapter I is amended as follows:
PART 180--[AMENDED]
1. In part 180:
a. The authority citation for part 180 continues to read as
follows:
Authority: 21 U.S.C. 346a and 371.
b. By revising Sec. 180.407 to read as follows:
Sec. 180.407 Thiodicarb; tolerances for residues.
(a) General . Tolerances are established for the combined residues
of the insecticide thiodicarb (dimethyl N,N'-
[thiobis[[(methylimino)carbonyloxy]] bis[ethanimidothioate]) and its
metabolite methomyl (S-methyl N-[(methylcarbamoyl)
oxy]thioacetimidate) in or on the following food commodities or groups.
The time-limited tolerances expire and are revoked on the dates listed
in the following table:
----------------------------------------------------------------------------------------------------------------
Expiration/revocation
Commodity Parts per million date
----------------------------------------------------------------------------------------------------------------
Broccoli...................................................... 7.0 None
Cabbage....................................................... 7.0 None
Cauliflower................................................... 7.0 None
Corn, sweet grain (K + CWHR).................................. 2.0 None
Cottonseed.................................................... 0.4 None
Cottonseed hulls.............................................. 0.8 None
Leafy vegetables (except Brassica vegetables)................. 35 None
Soybean hulls................................................. 0.8 None
Soybeans...................................................... 0.2 None
----------------------------------------------------------------------------------------------------------------
(b) Section 18 emergency exemptions. [Reserved]
(c) Tolerances with regional registrations. [Reserved]
(d) Indirect or inadvertent residues. [Reserved]
PART 186--[AMENDED]
2. In part 186:
a. The authority citation for part 186 continues to read as
follows:
Authority: 21 U.S.C. 342, 348, and 701.
Sec. 186.5650 [Removed]
b. Section 186.5650 is removed.
[FR Doc. 97-22397 Filed 8-21-97; 8:45 am]
BILLING CODE 6560-50-F
