[Federal Register Volume 63, Number 179 (Wednesday, September 16, 1998)]
[Notices]
[Pages 49568-49574]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-24840]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-830; FRL 6025-8]


Notice of Filing of Pesticide Petitions

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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SUMMARY: This notice announces the initial filing of pesticidepetitions 
proposing the establishment of regulations for residues of certain

[[Page 49569]]

pesticide chemicals in or on various food commodities.
DATES: Comments, identified by the docket control number PF-830, must 
be received on or before October 16, 1998.
ADDRESSES: By mail submit written comments to: Public Information and 
Records Integrity Branch (7502C), Information Resources and Services 
Division, Office of Pesticide Programs, Environmental Protection 
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments 
to: Rm. 119, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Comments and data may also be submitted electronically to: opp-
[email protected]. Follow the instructions under ``SUPPLEMENTARY 
INFORMATION.'' No confidential business information should be submitted 
through e-mail.
    Information submitted as a comment concerning this document may be 
claimed confidential by marking any part or all of that information as 
Confidential Business Information (CBI). CBI should not be submitted 
through e-mail. Information marked as CBI will not be disclosed except 
in accordance with procedures set forth in 40 CFR part 2. A copy of the 
comment 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. All written comments will be 
available for public inspection in Rm. 119 at the address given above, 
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal 
holidays.

FOR FURTHER INFORMATION CONTACT: The product manager listed in the 
table below:

------------------------------------------------------------------------
                                   Office location/                     
        Product Manager            telephone number          Address    
------------------------------------------------------------------------
Beth Edwards,.................  Rm. 216, CM #2, 703-    1921 Jefferson  
                                 305-5400; e-mail:       Davis Hwy.,    
                                 edwards.beth@epamail.   Arlington, VA  
                                 epa.gov.                               
Treva Alston,.................  Rm. 707B, CM #2, 703-   Do.             
                                 308-8373; e-mail:                      
                                 alston.treva@epamail.
epa.gov.                               
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SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as 
follows proposing the establishment and/or amendment of regulations for 
residues of certain pesticide chemicals in or on various food 
commodities under section 408 of the Federal Food, Drug, and Comestic 
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions 
contain data or information regarding the elements set forth in section 
408(d)(2); however, EPA has not fully evaluated the sufficiency of the 
submitted data at this time or whether the data supports granting of 
the petition. Additional data may be needed before EPA rules on the 
petition.
    The official record for this notice of filing, as well as the 
public version, has been established for this notice of filing under 
docket control number PF-830 (including comments and data submitted 
electronically as described below). 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 official record is located at the address in 
``ADDRESSES'' at the beginning of this document.
    Electronic comments can be sent directly to EPA at:
    [email protected]


    Electronic comments must be submitted as an ASCII file avoiding the 
use of special characters and any form of encryption. Comments and data 
will also be accepted on disks in Wordperfect 5.1/6.1 or ASCII file 
format. All comments and data in electronic form must be identified by 
the docket control number PF-830 and appropriate petition number. 
Electronic comments on this notice may be filed online at many Federal 
Depository Libraries.

List of Subjects

    Environmental protection, Agricultural commodities, Feed additives, 
Food additives, Pesticides and pests, Reporting and recordkeeping 
requirements.

    Dated: September 2, 1998.

James Jones,
Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

    Petitioner summaries of the pesticide petitions are printed below 
as required by section 408(d)(3) of the FFDCA. The summaries of the 
petitions were prepared by the petitioners and represent the views of 
the petitioners. EPA is publishing the petition summaries verbatim with 
minor, non-substantive editorial changes. The petition summary 
announces the availability of a description of the analytical methods 
available to EPA for the detection and measurement of the pesticide 
chemical residues or an explanation of why no such method is needed.

1. Dow AgroSciences

PP 8F5002

    EPA has received a pesticide petition (PP 8F5002) from Dow 
AgroSciences, 9330 Zionsville Road, Indianapolis, IN 46254 proposing 
pursuant to section 408(d) of the (FF DCA), 21 U.S.C. 346a(d), to amend 
40 CFR part 180 by establishing a tolerance for residues of the 
insecticide spinosad in or on the raw agricultural commodities corn 
grain including field, sweet (K+CWHR), and pop at 0.02 part per million 
(ppm); forage, fodder, straw, and hay of cereal grains at 1.0 ppm; 
legume vegetables (succulent including soybeans) at 0.3 ppm; cucurbits 
at 0.3 ppm; sorghum grain at 1.0 ppm; sorghum aspirated grain fractions 
at 3.0 ppm; stone fruit at 0.2 ppm; and wheat grain at 0.02 ppm. 
Because of the amount of spinosad residue found in corn, sorghum, and 
wheat products used in animal feeds as well as those commodities with 
existing residue tolerances that are potentially used in animal 
rations, the following increases in livestock residue tolerances are 
being proposed: livestock, meat residue tolerance of 0.1 ppm; 
livestock, meat byproduct residue tolerance of 0.4 ppm; livestock, fat 
residue tolerance of 1.5 ppm; a milk residue tolerance of 0.1 ppm; a 
milk fat residue tolerance of 1.5 ppm. In addition, the following 
poultry residue tolerances are being proposed: poultry, fat at 0.2 ppm; 
poultry, meat and meat byproducts at 0.02 ppm; and eggs at 0.02 ppm. An 
adequate analytical method is available for enforcement purposes. EPA 
has determined that the petition contains data or information regarding 
the elements set forth in section 408(d)(2) of the FFDCA; however, EPA 
has not fully evaluated the sufficiency of the submitted data at this 
time or whether the data supports granting of the petition. Additional 
data may be needed before EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. The metabolism of spinosad in plants (apples, 
cabbage, cotton, tomato, and turnip) and animals

[[Page 49570]]

(goats and poultry) is adequately understood for the purposes of these 
tolerances. A rotational crop study showed no carryover of measurable 
spinosad related residues in representative test crops.
    2. Analytical method. There is a practical method (immunoassay) for 
detecting 0.005 ppm and measuring 0.01 ppm levels of spinosad in or on 
food with a limit of detection that allows monitoring of food with 
residues at or above the levels set for these tolerances. The method 
has had a successful method tryout in the EPA's laboratories.
    3. Magnitude of residues. Magnitude of residue studies were 
conducted for stone fruit (7 sites for cherries, 6 sites for peaches, 4 
sites for plums, and 2 sites for prunes); cucurbits (6 sites for 
cucumbers, 6 sites for muskmelons, and 3 sites for summer squash); 
sweet corn (12 sites); field corn (5 sites at 5 x label rate); legume 
vegetables (11 sites for snap beans, 7 sites for snow peas, and 7 sites 
at 5 x label rate for soybeans); sorghum (9 sites); and wheat (6 sites 
at 5 x label rate). Residues found in these studies ranged from ND to 
0.14 ppm on stone fruit; ND to 0.19 ppm in cucurbits; ND for field corn 
grain and sweet corn (K=CWHR); 0.09 to 0.57 ppm for corn forage; 0.03 
to 0.82 ppm for corn fodder; ND to 0.23 ppm for legume vegetables; 0.03 
to 0.68 ppm for sorghum grain; 0.06 to 0.18 ppm for sorghum forage; 
0.06 to 0.29 ppm for sorghum fodder; 2.02 ppm for sorghum aspirated 
grain fractions; ND to 0.09 ppm for wheat grain; ND to 0.07 ppm for 
wheat forage; 0.01 to 0.20 ppm for wheat hay; and 0.01 to 0.73 ppm for 
wheat straw.

B. Toxicological Profile

    1. Acute toxicity. Spinosad has low-acute toxicity. The rat oral 
LD50 is 3,738 milligram/kilogram (mg/kg) for males and > 
5,000 mg/kg for females, whereas the mouse oral LD50 is > 
5,000 mg/kg. The rabbit dermal LD50 is > 5,000 mg/kg and the 
rat inhalation LC50 is > 5.18 mg/1 air. In addition, 
spinosad is not a skin sensitizer in guinea pigs and does not produce 
significant dermal or ocular irritation in rabbits. End use 
formulations of spinosad that are water based suspension concentrates 
have similar low acute toxicity profiles.
    2. Genotoxicty. Short-term assays for genotoxicity consisting of a 
bacterial reverse mutation assay (Ames test), an in vitro assay for 
cytogenetic damage using the Chinese hamster ovary cells, an in vitro 
mammalian gene mutation assay using mouse lymphoma cells, an in vitro 
assay for DNA damage and repair in rat hepatocytes, and an in vivo 
cytogenetic assay in the mouse bone marrow (micronucleus test) have 
been conducted with spinosad. These studies show a lack of 
genotoxicity.
    3. Reproductive and developmental toxicity. Spinosad caused 
decreased body weights in maternal rats given 200 mg/kg/day by gavage 
(highest dose tested). This was not accompanied by either embryo 
toxicity, fetal toxicity, or teratogenicity. The no-observed-effect 
levels (NOELs) for maternal and fetal toxicity in rats were 50 and 200 
mg/kg/day, respectively. A teratology study in rabbits showed that 
spinosad caused decreased body weight gain and a few abortions in 
maternal rabbits given 50 mg/kg/day (highest dose tested). Maternal 
toxicity was not accompanied by either embryo toxicity, fetal toxicity, 
or teratogenicity. The NOELs for maternal and fetal toxicity in rabbits 
were 10 and 50 mg/kg/day, respectively. In a two-generation 
reproduction study in rats, parental toxicity was observed in both 
males and females given 100 mg/kg/day (highest dose tested). Perinatal 
effects (decreased litter size and pup weight) at 100 mg/kg/day were 
attributed to maternal toxicity. The NOEL for maternal and pup effects 
was 10 mg/kg/day.
    4. Subchronic toxicity. Spinosad was evaluated in 13-week dietary 
studies and showed NOELs/no-observed-adverse-effect levels (NOAELs) of 
4.89 and 5.38 mg/kg/day, respectively in male and female dogs; 6 and 8 
mg/kg/day, respectively in male and female mice; and 33.9 and 38.8 mg/
kg/day, respectively in male and female rats. No dermal irritation or 
systemic toxicity occurred in a 21-day repeated dose dermal toxicity 
study in rabbits given 1,000 mg/kg/day.
    5. Chronic toxicity. Based on chronic testing with spinosad in the 
dog and the rat, the EPA has set a reference dose (RfD) of 0.027 mg/kg/
day for spinosad. The RfD has incorporated a 100-fold safety factor to 
the NOELs found in the chronic dog study to account for inter- and 
intra-species variation. The NOELs shown in the dog chronic study were 
2.68 and 2.72 mg/kg/day, respectively for male and female dogs. The 
NOELs (systemic) shown in the rat chronic/carcinogenicity/neurotoxicity 
study were 9.5 and 12.0 mg/kg/day, respectively for male and female 
rats. Using the Guidelines for Carcinogen Risk Assessment published 
September 24, 1986 (51 FR 33992), it is proposed that spinosad be 
classified as Group E for carcinogenicity (no evidence of 
carcinogenicity) based on the results of carcinogenicity studies in two 
species. There was no evidence of carcinogenicity in an 18-month mouse 
feeding study and a 24-month rat feeding study at all dosages tested. 
The NOELs shown in the mouse oncogenicity study were 11.4 and 13.8 mg/
kg/day, respectively for male and female mice. A maximum tolerated dose 
was achieved at the top dosage level tested in both of these studies 
based on excessive mortality. Thus, the doses tested are adequate for 
identifying a cancer risk. Accordingly, a cancer risk assessment is not 
needed.
    6. Animal metabolism. There were no major differences in the 
bioavailability, routes or rates of excretion, or metabolism of 
spinosyn A and spinosyn D following oral administration in rats. Urine 
and fecal excretions were almost completed in 48-hours post-dosing. In 
addition, the routes and rates of excretion were not affected by 
repeated administration.
    7. Metabolite toxicology. The residue of concern for tolerance 
setting purposes is the parent material (spinosyn A and spinosyn D). 
Thus, there is no need to address metabolite toxicity.
    8. Neurotoxicity. Spinosad did not cause neurotoxicity in rats in 
acute, subchronic, or chronic toxicity studies.
    9. Endocrine effects. There is no evidence to suggest that spinosad 
has an effect on any endocrine system.

C. Aggregate Exposure

    1. Dietary exposure. For purposes of assessing the potential 
dietary exposure from use of spinosad on stone fruit, cucurbits, corn 
(field, sweet, and pop), legume vegetables (succulent including 
soybeans), sorghum, and wheat as well as from other existing spinosad 
crop uses, a conservative estimate of aggregate exposure is determined 
by basing the theoretical maximum residue concentrations (TMRC) on the 
proposed tolerance levels for spinosad and assuming that 100% of these 
proposed new crops and other existing (registered for use) crops grown 
in the United States were treated with spinosad. The TMRC is obtained 
by multiplying the tolerance residue levels by the consumption data 
which estimates the amount of crops and related foodstuffs consumed by 
various population subgroups. The use of a tolerance level and 100% of 
crop treated clearly results in an overestimate of human exposure and a 
safety determination for the use of spinosad on crops cited in this 
summary that is based on a conservative exposure assessment.
    2. Drinking water. Another potential source of dietary exposure are 
residues in drinking water. Based on the available environmental 
studies conducted with spinosad wherein it's properties show little or 
no mobility in soil, there is no anticipated exposure to residues of 
spinosad in drinking water.

[[Page 49571]]

 In addition, there is no established maximum concentration level (MCL) 
for residues of spinosad in drinking water.
    3. Non-dietary exposure. Spinosad is currently registered for use 
on a number of crops including cotton, fruits, and vegetables in the 
agriculture environment. Spinosad is also currently registered for 
outdoor use on turf and ornamentals at low rates of application (0.04 
to 0.54 lb active ingredient (a.i.) per acre) and indoor use for 
drywood termite control (extremely low application rates used with no 
occupant exposure expected). Thus, the potential for non-dietary 
exposure to the general population is considered negligible.

D. Cumulative Effects

    The potential for cumulative effects of spinosad and other 
substances that have a common mechanism of toxicity is also considered. 
In terms of insect control, spinosad causes excitation of the insect 
nervous system, leading to involuntary muscle contractions, prostration 
with tremors, and finally paralysis. These effects are consistent with 
the activation of nicotinic acetylcholine receptors by a mechanism that 
is clearly novel and unique among known insecticidal compounds. 
Spinosad also has effects on the Gamma aminobatopic acid (GABA) 
receptor function that may contribute further to its insecticidal 
activity. Based on results found in tests with various mammalian 
species, spinosad appears to have a mechanism of toxicity like that of 
many amphiphilic cationic compounds. There is no reliable information 
to indicate that toxic effects produced by spinosad would be cumulative 
with those of any other pesticide chemical. Thus it is appropriate to 
consider only the potential risks of spinosad in an aggregate exposure 
assessment.

E. Safety Determination

    1. U.S. population. Using the conservative exposure assumptions and 
the proposed RfD described in Unit 1.B.5 of this document, the 
aggregate exposure to spinosad use on stone fruit, cucurbits, corn 
(field, sweet, and pop), legume vegetables (succulent including 
soybeans), sorghum, and wheat and other existing crop uses will utilize 
25.4% of the RfD for the U.S. population. A more realistic estimate of 
dietary exposure and risk relative to a chronic toxicity endpoint is 
obtained if average (anticipated) residue values from field trials are 
used. Inserting the average residue values in place of tolerance 
residue levels produces a more realistic, but still conservative risk 
assessment. Based on average or anticipated residues in a dietary risk 
analysis, the use of spinosad on the list in this unit of pending crop 
uses and other existing crop uses will utilize 4.0% of the RfD for the 
U.S. population. EPA generally has no concern for exposures below 100% 
of the RfD because the RfD represents the level at or below which daily 
aggregate dietary exposure over a lifetime will not pose appreciable 
risks to human health. Thus, it is clear that there is reasonable 
certainty that no harm will result from aggregate exposure to spinosad 
residues on existing and pending crop uses.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of spinosad, data from 
developmental toxicity studies in rats and rabbits and a 2-generation 
reproduction study in the rat are considered. The developmental 
toxicity studies are designed to evaluate adverse effects on the 
developing organism resulting from pesticide exposure during prenatal 
development. Reproduction studies provide information relating to 
effects from exposure to the pesticide on the reproductive capability 
and potential systemic toxicity of mating animals and on various 
parameters associated with the well-being of pups.
    FFDCA section 408 provides that EPA may apply an additional safety 
factor for infants and children in the case of threshold effects to 
account for pre- and post-natal toxicity and the completeness of the 
database. Based on the current toxicological data requirements, the 
database for spinosad relative to pre- and post-natal effects for 
children is complete. Further, for spinosad, the NOELs in the dog 
chronic feeding study which was used to calculate the RfD (0.027 mg/kg/
day) are already lower than the NOELs from the developmental studies in 
rats and rabbits by a factor of more than 10-fold.
    Concerning the reproduction study in rats, the pup effects shown at 
the highest dose tested were attributed to maternal toxicity. 
Therefore, it is concluded that an additional uncertainty factor is not 
needed and that the RfD at 0.027 mg/kg/day is appropriate for assessing 
risk to infants and children.
    In addition, the EPA has determined that the 10 x factor to account 
for enhanced sensitivity of infants and children is not needed because:
    i. The data provided no indication of increased susceptibility of 
rats or rabbits to in utero and/or post-natal exposure to spinosad. In 
the prenatal developmental toxicity studies in rats and rabbits and 2-
generation reproduction in rats, effects in the offspring were observed 
only at or below treatment levels which resulted in evidence of 
parental toxicity.
    ii. No neurotoxic signs have been observed in any of the standard 
required studies conducted.
    iii. The toxicology data base is complete and there are no data 
gaps.
    Using the conservative exposure assumptions previously described 
(tolerance level residues), the percent RfD utilized by the aggregate 
exposure to residues of spinosad on stone fruits, cucurbits, corn 
(field, sweet, and pop), legume vegetables (succulent including 
soybeans), sorghum and wheat and existing crop uses is 51.0% for 
children 1 to 6 years old, the most sensitive population subgroup. If 
average or anticipated residues are used in the dietary risk analysis, 
the use of spinosad on these crops will utilize 9.2% of the RfD for 
children 1 to 6 years old. Thus, based on the completeness and 
reliability of the toxicity data and the conservative exposure 
assessment, it is concluded that there is a reasonable certainty that 
no harm will result to infants and children from aggregate exposure to 
spinosad residues on the above proposed including existing crop uses.

F. International Tolerances

     There are no Codex Maximum Residue Levels established for residues 
of spinosad on stone fruit, cucurbits, corn (field, sweet, and pop), 
legume vegetables (succulent including soybeans), sorghum, and wheat or 
any other food or feed crop. (Beth Edwards)

2. Zeneca Ag Products

PP 6F3344

    EPA has previously received a pesticide petition (PP 6F3344) from 
Zeneca Ag Products, 1800 Concord Pike, Wilmington, DE proposing 
pursuant to section 408(d) of the (FFDCA), 21 U.S.C 346a(d) to amend 40 
CFR part 180 by establishing tolerances for the inert ingredient 
safener N,N-diallyl dichloroacetamide (dichlormid) of 0.05 ppm when 
applied to the raw agricultural commodities field corn grain, field 
corn fodder and field corn forage. Based on that petition EPA 
established time-limited tolerances on March 18, 1994, contingent upon 
submission of data from two chronic feeding/oncogenicity studies. The 
registrant provided those data on March 27, 1998, and is herein 
proposing that EPA extend that petition and remove the time-limitations 
previously imposed. EPA has determined that the petition contains data 
or information regarding the elements set forth in section 408(d)(2) of 
the FFDCA;

[[Page 49572]]

however EPA has not fully evaluated the sufficiency of the submitted 
data at this time or whether the data supports granting of the 
petition. Additional data may be needed before EPA rules on the 
petition.

A. Residue Chemistry

    1. Plant metabolism. The metabolism of dichlormid in corn plants is 
understood for the purposes of the proposed tolerances. The metabolism 
of dichlormid in corn is extensive and rapid. The principle route 
involves the displacement of the chlorine atoms, probably through 
glutathione mediated reductive dechlorination, followed by oxidation to 
N,N-diallyl glycolamide. The glycolamide is subsequently further 
oxidized to form the oxamic acid or conjugated with natural sugars. The 
presence of 14CO2 evolved from the plants 
following treatment of the soil demonstrates the catabolism of the 
14C atom and its probable inclusion in natural biosynthetic 
pathways. EPA has previously determined that dichlormid is the residue 
of concern for tolerance setting purposes.
    2. Analytical methods. An enforcement method is available and 
involves extraction, filtration, and concentration, followed by 
analysis by Gas Liquid Chromatography (GLC) with a selective thermionic 
detector. The method has been validated by the EPA at the Beltsville 
laboratory and included in the Pesticide Analytical Manual, Vol. II 
(PAM II). The validated limit of quantitation of the method allows 
monitoring of field corn and processed fractions at the proposed 
tolerances for dichloromid of 0.05 ppm.
    3. Magnitude of the residues. Many crop residue field trials have 
been conducted on field corn covering the major growing areas in the 
United States with dichlormid applied pre emergence at application 
rates up to 1.0 lb a.i. per acre. In all trials dichloromid residues in 
grain and processed fractions were all < 0.05 ppm. In a separate trial 
corn was treated with two applications of dichlormid (one pre emergence 
and one post emergence) at a rate of 0.83 lb a.i. per acre (to simulate 
an exaggerated rate of 1.66 lb a.i. per acre). Samples of grain from 
this trial were processed under conditions which simulated commercial 
practice. Dichlormid residues in grain and processed fractions were all 
< 0.05 ppm. Dichlormid has been shown to be stable in field corn crop 
fractions for a minimum of 3 years when stored at -18  deg.C. No 
transfer of residues to animals through the diet is expected.

B. Toxicological Profile

    1. Acute toxicity. Dichlormid has low acute toxicity, available 
data include: two rat acute oral studies with LD50's of 
2,080 mg/kg for males/2,030 for females and 2,816 mg/kg for males and 
2,146 mg/kg for females, respectively; a rat acute dermal study with an 
LD50 of > 2,040 mg/kg and a rabbit acute dermal study with 
an LD50 of > 5,000 mg/kg; two rat inhalation studies with 
LC50's of > 5.5 mg/l and > 5.6 mg/l, respectively; two 
primary eye irritation studies in the rabbit showing no irritation and 
slight irritation, respectively; two primary dermal irritation studies 
in the rabbit showing mild to moderate skin irritation, and a skin 
sensitization study which showed that dichlormid was a mild skin 
sensitizer in the guinea pig.
    2. Genotoxicity. Dichlormid was not mutagenic in a range of in 
vitro assays including the Salmonella/microsome (Ames) assay, the human 
lymphocyte cytogenetic assay (both assays with and without metabolic 
activation) and an unscheduled DNA synthesis (DNA repair) assay in 
hepatocytes. In the L5178Y mouse lymphoma assay small increases in 
mutant frequency were observed only at cytotoxic concentrations and 
were not considered to be significant. In vivo, dichlormid was negative 
in the mouse micronucleus test and in the rat unscheduled DNA synthesis 
assay, when tested at the maximum tolerated dose.
    3. Developmental toxicity. i. In an initial rat developmental 
effects study, previously submitted and accepted by EPA, female albino 
rats were dosed at 0, 10, and 40 mg/kg dichlormid in the diet from days 
6 through 15 of gestation and a NOEL of 40 mg/kg/day for both maternal 
toxicity and developmental toxicity was determined.
    ii. In a second study, rats were dosed orally by gavage with 0, 10, 
40, or 160 mg/kg/day. The NOEL for maternal toxicity was 10 mg/kg/day 
based on a reduction in bodyweight gain and food consumption at 40 and 
160 mg/kg/day. The developmental NOEL was determined to be 40 mg/kg/day 
based on marginal foetotoxic effects, including extra 14th ribs 
probably due to maternal stress, slight sternebra misalignment and some 
centra unossification, at 160 mg/kg/day.
    iii. In an additional developmental effects study, rabbits were 
dosed orally by gavage with 0, 5, 30, or 180 mg/kg/day. The lowest-
observed-effect level (LOEL) for both maternal and foetotoxicity was 
180 mg/kg/day, characterized by reduced body weight gain and food 
consumption and a small increase in post-implantation loss, partial 
ossification and misshapen/fused sternebrae. The NOEL for both maternal 
and developmental toxicity was 30 mg/kg/day.
    4. Subchronic toxicity. i. In an initial 90 day subchronic oral 
feeding study in the rat, previously submitted and accepted by EPA, 
animals were dosed at 0, 10, 40, and 160 mg/kg/day in the diet and a 
NOEL of 10 mg/kg/day was established.
    ii. In a second study, groups of 12 male and 12 female Wistar-
derived alpk: APfSD rats were fed diets containing 0, 20, 200, or 2,000 
ppm dichlormid for 90 days. Significant reductions in body/weight gain 
and food consumption were seen in male and female rats receiving 2,000 
ppm dichlormid and to a lesser degree in females at 200 ppm. The liver 
was identified as the principal target organ (enlargement, increased 
(APDM) activity in females, centrilobular hypertrophy, increased bile 
duct pigmentation) in the 2,000 ppm group. The NOEL was 20 ppm 
(equivalent to approximately 1 mg/kg/day (see discussion under Chronic 
toxicity in Unit 2.B.5. of this document) and the LOEL was 200 ppm, 
based on reduced body/weight gain and food consumption and a marginal 
increase in APDM activity in females and liver enlargment in males.
    iii. In 90-day dog feeding study, previously submitted and accepted 
by EPA, animals were dosed (4 dogs/sex/dose) at 0, 1, 5, 25, and 50 mg/
kg/day. The NOEL was 5 mg/kg/day and the LOEL 25 mg/kg/day based on 
reduced bodyweight gain, degenerative changes in voluntary muscle and 
increased liver weight with an associated increase in plasma alkaline 
phosphatase activity.
    iv. In a 14-week rat inhalation study, groups of 18 Sprague-Dawley 
CD rats were subjected to a whole body exposure of 0, 2.0, 19.9, or 
192.5 mg/m3 for 6 hours per day, 5 days per week. The NOEL 
was 2.0 mg/m3 based on histopathologic tissue alterations to 
the nasal olfactory epithelium at 19.9 and 192.5 mg/m3, 
suggesting that dichlormid was a mild irritant to the nasal cavity. An 
increase in relative liver, kidney, and lung weights, that was not 
supported by gross or histopathological observations, was considered 
due to a combination of stress and inappetance at 19.9 and 192.5 mg/
m3.
    5. Chronic toxicity. Rats (64/sex/group) were fed diets containing 
0, 20, 100, or 500 ppm dichlormid (0, 1.3, 6.5, 32.5 mg/kg/day for 
males and 0, 1.5, 7.5, 37.5 mg/kg/day for females) for up to 2 years. 
At 500 ppm in both males and females there were treatment-related 
effects on growth and food consumption, minor reductions in

[[Page 49573]]

plasma triglycerides and in males, increased liver weights, accompanied 
by hepatocyte vaculolation and pigmentation effects. In females there 
was a slight overall increase in malignant tumors, primarily uterine 
adenocarcinomas, at 500 ppm but this specific increase was within the 
spontaneous incidence observed within historical control values. It was 
concluded that there was no evidence of oncogenicity associated with 
dichlormid treatment. The NOEL for chronic toxicity was 100 ppm (6.5 
and 7.5 mg/kg/day for males and females respectively). In an 18-month 
oncogenicity study, mice (55/sex/group) were fed dichlormid at doses of 
0, 10, 50, or 500 ppm (0, 1.4, 7.0, 70 mg/kg for males and 0, 1.84, 
9.2, 92 mg/kg for females). At 500 ppm there was a slight increase in 
mortality for females from week 64 onwards and bodyweights and food 
utilization were reduced in males, and to a lesser extent in females. 
Also mice fed 500 ppm dichlormid showed non-neoplastic changes which 
were minor and consisted of changes in severity or incidence of common 
spontaneous findings. Based on these effects, the chronic NOEL was 50 
ppm (7.0 and 9.2 mg/kg/day for males and females respectively). There 
was a marginal increase in Harderian gland adenomas in males at 500 ppm 
but this was considered to reflect the variable spontaneous tumor rate 
seen in this strain and sex of mouse. It was concluded there was no 
evidence of oncogenicity associated with dichormid treatment.
    Based on available chronic toxicity data, Zeneca believes the RfD 
for dichlormid is 0.07 mg/kg/day. This RfD is based on the 2-year 
feeding study in rats with an NOEL of 7 mg/kg/day. An uncertainty 
factor of 100 was used to account for inter-species extrapolation and 
intra-species variability. The 2 year rat study is consistent with, but 
supersedes, the 90 day rat study. The 2 year rat NOEL of 7 mg/kg/day 
lies between 1.7 and 17 mg/kg/day derived from the NOEL and LOEL 
figures of 20 and 200 ppm respectively for the most recent 90 day rat 
study. Thus the overall NOEL in the rat for both chronic and subchronic 
exposure should be regarded as 7 mg/kg/day. Based on the proposed 
Guidelines for Carcinogenic Risk Assessment (April 23, 1996) Zeneca 
believes that dichlormid is not likely to be a human carcinogen, and a 
margin of exposure (MOE) approach should be used for human risk 
assessment.
    6. Animal metabolism. In the rat dichlormid is readily absorbed and 
fairly rapidly excreted with extensive metabolism; the major route 
results in the formation of N,N-diallylglycolamide and its glucuronide 
conjugate. The glycolamide is subsequently oxidized to the N,N-
diallyloxamic acid. An alternative pathway involves cleavage of 
dichlormid to form dichloroacetic acid, which was also a significant 
urinary metabolite. The further biotransformation of this metabolite 
and of N,N-diallyloxamic acid would lead to the observed evolution of 
carbon dioxide.
    7. Metabolite toxicity. No unique plant or soil metabolites have 
been identified that warrant a separate toxicological assessment.
    8. Endocrine disruption. No specific tests have been conducted with 
dichlormid to determine whether the chemical may have an effect in 
humans that is similar to an effect produced by a naturally occurring 
estrogen or other endocrine effects. However, there is no overall trend 
in the toxicology database that indicates that dichlormid would have 
endocrine disrupting activity.

C. Aggregate Exposure

    1. Food. To assess the potential dietary exposure using the 
proposed tolerances of 0.05 ppm, Zeneca has estimated the aggregate 
exposure based on the theoretical maximum residue contribution (TMRC). 
This is a highly conservative over-estimation of human exposure, based 
on tolerance level residues (0.05 ppm) and 100% crop treated. The 
analysis was determined using the DEEM software and the USDA CSF II 94-
95 data.
    2. Drinking water. Dichlormid is very rapidly degraded in soil ( 
laboratory measured aerobic half life of 8 days), and applied at a 
maximum rate of 1.0 lb/acre, so despite only exhibiting moderate 
adsorption to soil, (Koc 36-49), the leaching potential for dichlormid 
to reach ground water is expected to be low. The impact of the 
interactive processes of adsorption and degradation on leaching have 
been assessed using EPA mathematical models of pesticide movement in 
soil.
    Drinking water estimate concentrations (DWEC) were calculated using 
(SCI-GROW) and (GENEEC). These predict a ground water concentration of 
0.02 ppb, and surface water concentrations of 49.71 ppb for an 
instaneous peak and 49.27 for a 56 day average. Drinking water levels 
of concern (DWLOC) were calculated for both chronic and acute exposure 
according to the EPA (SOP). All the values are less than the DWEC. As 
EPA believes there is negligible risk at values less than 100% of the 
DWEC, Zeneca does not expect exposure to dichlormid residues in 
drinking water to be a concern.
    3. Non-dietary exposures. As dichlormid is used only on 
agricultural crops and is not used in or around the home, exposure to 
the general population is unlikely.

D. Cumulative Effects

    Zeneca has considered the potential for cumulative effects of 
dichlormid and other substances that have a common mechanism of 
toxicity. Zeneca does not have any reliable information to suggest that 
dichlormid has any toxic effects that arise from toxic mechanisms, that 
are common to other substances. Therefore, a consideration of common 
mechanism and cumulative effects with other substances is not 
appropriate for dichlormid and Zeneca is considering only the potential 
risks of dichlormid in this exposure assessment.

E. Safety Determination

    1. U.S. population--i. Chronic risk. Using the conservative 
exposure assumptions described above and based on the completeness and 
reliability of the toxicity data base for dichlormid, Zeneca has 
calculated the aggregate exposure will be 0.1% (0.00006 mg/kg/day) of 
the RfD (0.07 mg/kg/day) for the U.S population. The most highly 
exposed subgroup is non-nursing infants a TMRC of 0.000149 mg/kg/day or 
0.27% of the RfD. As EPA generally has no concern for exposures below 
100% of the RfD because the RfD represents the level at or below which 
daily aggregate dietary exposure over a lifetime will not pose 
appreciable risks to human health, Zeneca concludes that there is a 
reasonable certainty that no harm will result from aggregate exposure 
to dichlormid residues.
    ii. Acute risk. The acute toxicity of dichlormid is low, and there 
are no concerns for acute-dietary, occupational or non-occupational 
exposures to dichlormid.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of dichlormid, data 
from developmental toxicity studies in the rat and rabbit have been 
considered. The developmental toxicity studies are designed to evaluate 
adverse effects on the developing organism resulting from maternal 
pesticide exposure during gestation. There was no evidence to suggest 
that dichlormid was a developmental toxicant in either the rat or 
rabbit. It was also observed that there was no risk below maternally 
toxic doses as the NOEL for developmental effects in the rat was 40 mg/
kg/day as opposed to the maternal NOEL of 10

[[Page 49574]]

mg/kg/day and, in the rabbit study, the NOEL for both maternal and 
developmental effects was 30 mg/kg/day. For both these reasons, and the 
fact that the RfD is based on the chronic rat study which has a NOEL 
considerably lower than the developmental NOELs, Zeneca believes that 
an additional uncertainty factor is not warranted for the safety of 
infants and children. Reliable data supports the use of a 100-fold 
uncertainty factor (MOE) to account for inter-species extrapolation and 
intra-species variability which will be appropriate to protect infants 
and children. Using the same conservative exposure assumptions used for 
the determination in the general population, Zeneca has concluded that 
the percentage of RfD that will be utilized by aggregate exposure to 
dichlormid is 0.2% for non-nursing infants (the group at highest risk). 
Therefore, based on the completeness and reliability of the toxicity 
data base and the conservative exposure assessment, Zeneca concludes 
that there is a reasonable certainty that no harm will result to 
infants and children from aggregate exposure to dichlormid residues.

F. International Tolerances

    A Maximum Residue Level has not been established for dichlormid by 
the Codex Alimentarius Commission. (Treva Alston)

[FR Doc. 98-24840 Filed 9-15-98; 8:45 am]
BILLING CODE 6560-50-F