[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: <a href="/cdn-cgi/l/email-protection#8ee1fefea3eae1ede5ebfaceebfeefe3efe7e2a0ebfeefa0e9e1f8"><span class="__cf_email__" data-cfemail="4e213e3e632a212d252b3a0e2b3e2f232f2722602b3e2f60292138">[email protected]</span></a>. 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: 
<a href="/cdn-cgi/l/email-protection#365e5744445f4518425e595b5745765346575b575f5a1853465718515940"><span class="__cf_email__" data-cfemail="0e666f7c7c677d207a6661636f7d4e6b7e6f636f6762206b7e6f20696178">[email protected]</span></a>.

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 
LD<INF>50</INF> 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 LD<INF>50</INF> was 73 mg/kg 
in males and 79 mg/kg in females (MRID 43784501).
    The LD<INF>50</INF> 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 
LC<INF>50</INF> 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 (LD<INF>50)</INF> 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/m<SUP>3</SUP> for males, and 0, 
4.8, 19.6, and 54.0 mg/m<SUP>3</SUP> for females (mean measured 
atmospheric concentrations) for 6 hours a day for 9 days. The NOEL was 
not determined. At 4.8 mg/m<SUP>3,</SUP> 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/m<SUP>3</SUP> 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<SUP> </SUP>BR/VAF/Plus<SUP> </SUP> 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 LD<INF>50</INF> 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 LD<INF>50</INF> value for methomyl in rabbits was 
greater than 2000 mg/kg (Toxicity Category III) for both sexes (MRID 
42074602).
    The acute inhalation LC<INF>50</INF> 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 F<INF>0</INF> 
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 F<INF>1</INF> 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 
(<gr-thn-eq>40 mM = 6.5

[[Page 44588]]

mg/mL -S9; <gr-thn-eq>150 <greek-m>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 LD<INF>50</INF> 
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 <divide> Exposure = 5 mg/kg/day <divide> 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 <greek-m>g/L in ground and/or 
surface water) x (10<SUP>-3</SUP> mg/<greek-m>g) <divide> (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 <greek-m>g/L in ground and/or 
surface water) x (10<SUP>-3</SUP> mg/<greek-m>g) <divide> (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 <greek-m>g/L) x (10<SUP>-3</SUP> mg/<greek-m>g) <divide> (70 kg 
body weight) x (2L day) = 5.7 x 10<SUP>-4</SUP> mg/kg/day.
    Methomyl exposure (highest concentration modeled in surface water) 
= (30 <greek-m>g/L) x (10<SUP>-3</SUP> mg/<greek-m>g) <divide> (70 kg 
body weight) x (2L day) = 8.57 x 10<SUP>-4</SUP> mg/kg/day.
    The highest exposure number will be used for acute water risk 
assessment for <greek-m>g/L) x (10<SUP>-3</SUP> mg/<greek-m>g) <divide> 
(70 kg body weight) x (2L day) = 8.57 x 10<SUP>-4</SUP> mg/kg/day.
    b. Children's (1 to 6 years old) acute exposure.
    Methomyl exposure (highest concentration detected in ground water) 
= (20 <greek-m>g/L) x (10<SUP>-3</SUP> mg/<greek-m>g) <divide> (10 kg 
body weight) x (1L day) = 2.0 x 10<SUP>-3</SUP>mg/kg/day.
    Methomyl exposure (highest concentration modeled in surface water) 
= (30 <greek-m>g/L) x (10<SUP>-3</SUP> mg/<greek-m>g) <divide> (10 kg 
body weight) x (1L day) = 3.0 x 10<SUP>-3 </SUP>mg/kg/day.
    The highest exposure number will be used for acute water risk 
assessment for <greek-m>g/L) x (10<SUP>-3</SUP> mg/<greek-m>g) <divide> 
(10 kg body weight) x (1L day) = 3.0 x 10<SUP>-3 </SUP>mg/kg/day.
    c. Acute risk-water.
    NOEL//Exposure = MOE
    Adult (male) MOE = 6 mg/kg/day <divide> acute water exposure (8.57 
x 10<SUP>-4</SUP>mg/kg/day) = 7,001
    Children's MOE = 6 mg/kg/day <divide> acute water exposure(3 x 
10<SUP>-3 </SUP>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 <greek-m>g/L) x (10<SUP>-3</SUP> mg/<greek-m>g) <divide> (70 kg 
body weight) x (2L day) = 5.7 x 10<SUP>-5</SUP> mg/kg/day.
    Methomyl exposure (average concentration detected in surface water) 
= (26 <greek-m>g/L) x (10<SUP>-3</SUP> mg/<greek-m>g) <divide> (70 kg 
body weight) x (2L day) = 7.4 x 10<SUP>-4</SUP> mg/kg/day.
    The highest exposure number will be used for chronic water risk 
assessment = 7.4 x 10<SUP>-4</SUP>.
    b. Children's(1 to 6 years old) chronic exposure.
    Methomyl exposure (average concentration detected in ground water) 
= (2 <greek-m>g/L) x (10<SUP>-3</SUP> mg/<greek-m>g) <divide> (10 kg 
body weight) x (1L day) = 2.0 x 10<SUP>-4</SUP> mg/kg/day.
    Methomyl exposure (average concentration modeled in surface water) 
= (26 <greek-m>g/L) x (10<SUP>-3</SUP> mg/<greek-m>g) <divide> (10 kg 
body weight) x (1L day) = 2.6 x 10<SUP>-3</SUP> mg/kg/day.
    The highest exposure number will be used for acute water risk 
assessment for children = 2.6 x 10<SUP>-3</SUP>.
    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 <divide> RfD mg/kg/day x 100 = % 
RfD
    %RfD Adult (male) = 7.4 x 10<SUP>-4 </SUP> <divide> 0.008 mg/kg/day 
x 100 =9%RfD
    %RfD Children(1 to 6 years) = 2.6 x 10<SUP>-3 </SUP> <divide> 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 %RfD<SUP>a              Water %RfD                 Total<SUP>b        
----------------------------------------------------------------------------------------------------------------
U. S. General........................            1.9                       9                        11          
Children (1 to 6)....................            2.7                       33                       36          

[[Page 44592]]

                                                                                                                
Infants..............................            6.5                       33                      40           
----------------------------------------------------------------------------------------------------------------
<SUP>a  Dietary % RfD includes methomyl residues from application of thiodicarb and methomyl.                        
<SUP>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<SUP> </SUP>BR/VAF/Plus<SUP> </SUP> 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 
F<INF>0</INF> 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 F<INF>1</INF> 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<SUP>-3</SUP> ) from a Novigen Monte Carlo 
analysis and the acute water exposure number (8.57 x 10<SUP>-4</SUP>) 
were combined and resulted in an aggregate exposure of 7.43 x 
10<SUP>-3</SUP>. 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:
    <a href="/cdn-cgi/l/email-protection#523d22227f363d31393726123722333f333b3e7c3722337c353d24"><span class="__cf_email__" data-cfemail="bfd0cfcf92dbd0dcd4dacbffdacfded2ded6d391dacfde91d8d0c9">[email protected]</span></a>.


    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


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