[Federal Register Volume 63, Number 158 (Monday, August 17, 1998)]
[Notices]
[Pages 43937-43944]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-22012]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-819 FRL-6018-2]


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 pesticide 
petitions proposing the establishment of regulations for residues of 
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by the docket control number PF-819 must be 
received on or before September 16, 1998.
ADDRESSES: By mail submit written comments to: Public Information and 
Records Integrity Branch, Information Resources and Services Division 
(7502C), Office of Pesticides Programs, Environmental Protection 
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments 
to: Rm. 1132, 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. 1132 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    
------------------------------------------------------------------------
Joanne I. Miller..............  Rm. #227, CM #2, 703-   1921 Jefferson  
                                 305-6224, e-            Davis Hwy,     
                                 mail:miller.joanne@ep   Arlington, VA  
                                 amail.epa.gov.                         
Cynthia Giles-Parker..........  Rm. #247, CM #2, 703-   Do.             
                                 305-7740,e-mail:giles-
parker.cynthia@epamai
l.epa.gov.                             
------------------------------------------------------------------------

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-819] (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 file format or ASCII 
file format. All comments and data in electronic form must be 
identified by the docket number FRL-6018-2 and appropriate petition 
number. Electronic comments on notice may be filed online at many 
Federal Depository Libraries.

List of Subjects

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

    Dated:August 4, 1998.

Arnold E. Layne,

Acting 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 
without editing

[[Page 43938]]

them in any way. 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. BASF Corporation

PP 6F4640 and 3F4270

    EPA has received pesticide petitions (PP 6F4640 and 3F4270) from 
BASF Corporation, P.O. Box 13528, Research Triangle Park, NC 27709-3528 
proposing pursuant to section 408(d) of the Federal Food, Drug, and 
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by 
establishing tolerances for residues of bentazon (3-isopropyl-1H-2,1,3-
benzothiadiazin-4(3H)-one 2,2-dioxide) and its 6- and 8-hydroxy 
metabolites in or on the raw agricultural commodities succulent peas at 
3.0 parts per million (ppm) and flax seed at 1.0 ppm. Bentazon is 
currently registered for use in succulent peas with a 30-day preharvest 
interval (PHI) and a tolerance has been established at 0.5 ppm. The 
proposed increase in tolerance will allow for a reduction in the 
preharvest interval (PHI) to 10 days. EPA has determined that the 
petitions contain 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 petitions. Additional data may be needed 
before EPA rules on the petitions.

A. Residue Chemistry

    1. Plant metabolism. The qualitative nature of the residue in 
plants is adequately understood. Bentazon is rapidly metabolized, 
conjugated and incorporated into natural plant constituents. Metabolism 
involves the hydroxylation of bentazon at the 6- and 8-position. The 
terminal residues of regulatory concern are bentazon, 6-hydroxy 
bentazon, and 8-hydroxy bentazon (as specified in 40 CFR 180.355 (a)).
    2. Analytical method. Adequate enforcement methods are available in 
the Pesticide Analytical Manual (PAM) Vol. II for the determination of 
residues of bentazon and its 6- and 8-hydroxy metabolites in/on plant 
commodities and for the determination of bentazon and AIBA metabolite 
in animal commodities. The methods involve quantitation by gas 
chromatography with flame photometric or nitrogen-specific Coulson 
conductivity detectors. The limit of quantitation is 0.05 ppm in animal 
tissues and eggs, 0.02 ppm in milk, and 0.05 ppm in plants. Residue 
data submitted in support of the succulent pea and flax petitions were 
collected using modifications of the available PAM Vol. II methods. 
These modified methods, along with the methods listed in PAM Vol. II 
are adequate for bentazon data collection and tolerance enforcement.
    3. Magnitude of residues. Ten garden pea field trials were 
conducted in 7 States. Experimental plots were treated with two 
applications of bentazon at a rate of 1.0 lb ai/A/application. Samples 
of pea pods and vines were harvested from each treated plot 10 days 
after the second application. Samples were analyzed for the combined 
residues of bentazon and its 6- and 8-hydroxy metabolites. Analysis of 
treated samples showed that the maximum total combined residue was 2.9 
ppm in pods and 26.6 ppm in vines.
    Flax field trials were conducted in North Dakota (1 trial), South 
Dakota (2 trials), and Minnesota (1 trial). Experimental plots of flax 
were treated with two applications of bentazon at a rate of 1.0 lb ai/
A/ application. Samples of flax seed and straw were harvested at normal 
maturity, resulting in a PHI range of 43 to 47 days. The maximum 
combined residue (bentazon and its 6- and 8-hydroxy metabolites) in 
flax seed samples was 0.63 ppm and in flax straw was 4.9 ppm. In the 
processing study, there was no concentration of residue in flax meal. 
In the flax petition (PP 3F4270) tolerances were proposed for the 
combined residue of bentazon and its 6- and 8-hydroxy metabolites in or 
on flax seed at 1.0 ppm and flax straw at 6.0 ppm. Since this 
submission was made the regulations have changed and flax straw has 
been removed as a raw agricultural commodity (Residue Chemistry Test 
Guidelines, OPPTS 860.1000, August 1996) and a tolerance is no longer 
required. Therefore, the tolerance statement for PP 3F4270 has been 
amended proposing to establish a tolerance for the combined residues of 
the herbicide bentazon and its metabolites in/on flax seed only. The 
flax straw tolerance proposal has been removed.

B. Toxicological Profile

    1. Acute toxicity. Technical bentazon has been evaluated for acute 
toxicity effects. A summary of the acute toxicity studies follows:

                                                                        
                                                                        
                                                                        
                                                                        
Acute oral LD50 (rat)             1,100 mg/kg; M&F    Toxicity category 
                                                       III              
 Acute dermal LD50 (rat)          >2,500 mg/kg        Toxicity category 
                                                       III              
Eye irritation (rabbit)           Slight irritation   Toxicity category 
                                                       III              
Acute inhalation LC50 (rat)       >4.8 mg/l           Toxicity category 
                                                       IV               
 Dermal irritation (rabbit)       Minimal             Toxicity category 
                                                       III              
 Dermal sensitization (guin.                          Sensitizer.       
 pig)                                                                   
                                                                        

    2. Genotoxicty. Bentazon was not mutagenic in the tests for gene 
mutations, which were reverse mutation assays in S. typhimurium and in 
E. coli WP2 uvrA as well as forward mutation assays with in vitro 
Chinese hamster ovary cell (HGPRT) cultures. Bentazon was also negative 
in the mouse micronucleus test for assessing structural chromosomal 
aberrations and the unscheduled DNA synthesis assay with primary mouse 
hepatocytes for detecting DNA damage.
    3. Reproductive and developmental toxicity. Teratogenicity study--
Rat. In pregnant Wistar rats gavaged with 0, 40, 100, or 250 mg/kg/day 
of bentazon on gestation days 6-15, the maternal toxicity NOEL was over 
250 mg/kg/day. The developmental toxicity NOEL was 100 mg/kg/day. The 
LOEL was 250 mg/kg/day based upon an increase in postimplantation loss 
and a reduction of fetal body weights. In addition, there was an 
indication of delayed skeletal ossification of phalangeal nuclei of 
fore- and hind-limb digits, sternebrae, and cervical vertebrae. The 
delayed skeletal development was considered to be due

[[Page 43939]]

to a delayed maturation as indicated by the decreased fetal weight at 
this dose.
    4. Teratogenicity study-- Rabbit. When pregnant Chinchilla rabbits 
were gavaged with 75, 150, or 375 mg/kg/day, on gestation days 6-18, 
the maternal toxicity NOEL was 150 mg/kg/day. The maternal LOEL was 375 
mg/kg/day due to the occurrence in a single doe of a partial abortion, 
embryonic resorptions, and the absence of living fetuses. The 
developmental toxicity NOEL was over 375 mg/kg/day.
    5. Reproduction, 2-generation study-- Rat. A reproductive NOEL at 
200 ppm (approximately 15 mg/kg/day; lowest dose tested (LDT)) was 
found in a 2-generation study in Wistar rats. Doses were 0, 200, 800, 
or 3,200 ppm bentazon in the diet. Higher levels of 800 ppm 
(reproductive LOEL) and 3,200 ppm (approximately 62 and 249 mg/kg/day, 
respectively) were associated with a decrease in the body weights of 
the pups during lactation. For parental toxicity, the NOEL was 800 ppm, 
and the LOEL was 3,200 ppm based on reductions in food consumption and 
weight gain, and increased incidence of renal mineralization and liver 
microgranuloma.
    6. Subchronic toxicity--i. 90-day feeding study-- Rat. In a 13-week 
dietary feeding study in Wistar rats, the doses were 0, 400, 1,200, or 
3,600 ppm in the diet. The systemic toxicity NOEL was 1,200 ppm 
(equivalent to 60 mg/kg/day). The LOEL was 3,600 ppm (180 mg/kg/day; 
highest dose tested (HDT)) based on reductions in body weight gain, 
increased thromboplastin and prothrombin times, diuresis, clinical 
chemistry changes (e.g. increases in albumin, A/G ratios, and sodium), 
and increased kidney and liver weights. In addition, females in the 
3,600 ppm group showed suggestive evidence for the presence of lung 
thrombi and dilated uterine horns.
    ii. 21-day dermal. In a 21-day dermal study in rabbits, the doses 
were 0, 250, 500 and 1,000 mg/kg/day applied daily for 6 hours. There 
were no clinical signs of systemic toxicity at any dose level tested. 
The no adverse effect level (NOAEL) was > 1,000 mg/kg/day for male and 
female rabbits.
    7. Chronic toxicity--i. Chronic feeding study- non-rodent--Dog. 
Administration of bentazon in the feed of beagle dogs for 1 year at 
levels of 0, 100, 400, or 1,600 ppm resulted in a systemic toxicity 
NOEL of 100 ppm (approximately 3.2 mg/kg/day) and a LOEL of 400 ppm 
(approximately 13.1 mg/kg/day). Adverse toxicological effects at the 
two HDT consisted of clinical signs of toxicity (emaciation, 
dehydration, loose and/or bloody stools, pale mucous membranes, and 
reduced activity), hematological changes suggestive of anemia 
(decreased red cells, hemoglobin and hematocrit, abnormal red cell 
morphology, and increased reticulocytes, platelets, leukocytes, and 
partial thromboplastin time), depressed body weight gains, intestinal 
inflammation, and congestion of the small intestine and spleen. The 
anemia appeared to be due to blood loss from the gastrointestinal 
tract.
    ii. Chronic feeding/oncogenicity study-- Rat. Fischer 344 rats were 
given 0, 200, 800, or 4,000 ppm bentazon in the diet in a 2-year 
combined chronic toxicity-carcinogenicity study. The systemic toxicity 
NOEL was 200 ppm, equivalent to 10 mg/kg/day LDT. Adverse effects were 
observed at levels of 800 ppm (40 mg/kg/day; LOEL) and 4,000 ppm (200 
mg/kg/day) and consisted of increases in prothrombin time and partial 
thromboplastin time, increases in urine volume, blood urea nitrogen, 
and kidney weight along with reduced urinary specific gravity, a 
reduction in body weight gain, and a decrease in thyroid gland weight. 
No compound-related increase in tumors was observed.
    iii. Oncogenicity study-- Mouse. B6C3F1 mice were fed 0, 100, 400, 
or 2,000 ppm bentazon in a 2-year combined chronic toxicity-
carcinogenicity study. The systemic toxicity NOEL was 100 ppm, 
equivalent to 15 mg/kg/day LDT. Adverse effects were observed at levels 
of 400 ppm (60 mg/kg/day; LOEL) and 2,000 ppm (300 mg/kg/day). There 
were an increased prothrombin time, calcification of the tunica 
albuginea of the testes, hyperplasia of pancreatic islet cells and 
liver, slight increase in mortality, reduced weight gain, areas of 
hemorrhage in the liver and heart, and increased weights of the kidney, 
thyroid gland, and pituitary gland. No compound- related increase in 
tumors was observed.
    8. Animal metabolism. The qualitative nature of the residue in 
animals is adequately understood. Bentazon and its metabolite 2 amino-
N-isopropylbenzamide (AIBA) are the regulated terminal residues in 
animal tissues, eggs and milk.
    9. Endocrine disruption. No special studies investigating potential 
estrogenic or endocrine effects of bentazon have been conducted. 
However, the standard battery of required studies has been completed. 
These studies include an evaluation of the potential effects on 
reproduction and development, and an evaluation of the pathology 
exposure. These studies are generally considered to be sufficient to 
detect any endocrine effects but no such effects of the endocrine 
organs following repeated or long-term were noted in any of the 
studies.
    10. Neurotoxicity. No specific neurotoxicity studies have been 
conducted with bentazon. However, the results of acute, subchronic and 
chronic studies with bentazon in different animal species did not 
indicate evidence of any neurotoxic potential. It is assessed as being 
very unlikely that bentazon would pose a specific neurotoxic hazard.

C. Aggregate Exposure

    EPA has performed analyses to determine the risks from aggregate 
exposure to bentazon residues. For purposes of assessing the potential 
dietary exposure, EPA has estimated aggregate exposure based on the 
Theoretical Maximum Residue Contribution (TMRC) from: (i) all existing 
bentazon tolerances; and (ii) all existing tolerances plus the proposed 
increase in tolerance in succulent peas. The TMRC is a ``worst case'' 
estimate of dietary exposure since it is assumed that 100% of all crops 
for which tolerances are established are treated and that pesticide 
residues are at the tolerance levels.
    EPA published a dietary risk assessment for bentazon based on 
existing uses supported through reregistration in the Reregistration 
Eligibility Decision (RED) for bentazon dated January 27, 1995. EPA 
also published an aggregate risk assessment for bentazon based on 
existing tolerances plus a proposed increase in tolerance in succulent 
peas in a final rule in the FR 33563 (FRL 5720-4) (June 20, 1997). This 
final rule established a time-limited tolerance for bentazon and its 
metabolites in/on succulent peas at 3 ppm in connection with EPA's 
granting an emergency exemption under section 18 of the Federal 
Insecticide, Fungicide, and Rodenticide Act authorizing use of bentazon 
in/on succulent peas with a 10-day PHI in Minnesota, and Wisconsin. 
BASF used information/data from these documents and performed 
additional analyses in developing the following aggregate risk 
assessment.
    1. Dietary exposure. The TMRC for the overall U.S. population from 
existing bentazon tolerances supported through reregistration is 
estimated at 0.000651 mg/kg bwt/day, which represents 2.2% of the RfD. 
The TMRC for the overall U.S. population from the existing bentazon 
tolerances plus the proposed increase in tolerance for succulent peas 
is estimated at 0.001079 mg/kg bwt/day, which represents 3.6%

[[Page 43940]]

of the RfD. Thus, dietary exposure to residues of bentazon in or on 
food from the proposed tolerance increase in succulent peas will 
increase the TMRC by 1.4% of the RfD for the overall U.S. population.
    The TMRC from existing bentazon tolerances supported through 
reregistration for the most highly exposed subpopulation (non-nursing 
infants, <1- year old) is estimated at 0.002444 mg/kg bwt/day, which 
represents 8.1% of the RfD. The TMRC from the existing bentazon 
tolerances plus the proposed increase in tolerance for succulent peas 
for non-nursing infants (<1-year old) is estimated at 0.003755 mg/kg 
bwt/day, which represents 12.5% of the RfD. Dietary exposure to 
residues of bentazon in or on food from the proposed tolerance increase 
in succulent peas will increase the TMRC by 4.4 % of the RfD for non-
nursing infants (<1-year old). These exposure assessments rely on very 
conservative assumptions- 100% of crops will contain bentazon residues 
and those residues would be at the level of the tolerance- which 
results in an overestimate of human exposure.
    BASF believes that there will be no impact on the TMRC as a result 
of the use of bentazon in flax. No flax product is consumed by man as 
food and therefore the proposed tolerance will not directly impact the 
TMRC.
    2. Drinking water. To account for the exposure from drinking water, 
BASF used an exposure level of 20 ppb as previously used in the final 
rule establishing a time-limited tolerance for bentazon and its 
metabolites in/on succulent peas. This is a very conservative estimate 
since it is unlikely that a person would be exposed to this level daily 
for a life-time. BASF estimates that consumption of 2 liters of water 
per day by a 70 kg adult at a water exposure level of 20 ppb would 
result in an additional consumption of approximately 2.2% of the RfD. 
Using these very conservative estimates for food (3.6%) and water 
(2.2%) results in a total of 5.8% of the RfD for the U.S. population. 
Thus, BASF believes that even if all the water consumed by a person 
over a lifetime contained bentazon at 20 ppb there would still be 
nearly a twenty-fold level of safety.
    3. Non-dietary exposure. In the final rule establishing a time-
limited tolerance for bentazon and its metabolites in/on succulent 
peas, EPA discussed short- and intermediate-term exposure. According to 
EPA, short- and intermediate-term aggregate exposure takes into account 
chronic dietary food and water (considered to be a background exposure 
level) plus indoor and outdoor residential exposure. Although 
residential exposure data are not available for ornamentals and 
ornamental turf uses of bentazon, EPA noted that large MOEs were 
calculated for acute aggregate risk (>= 7,000) and occupational 
exposure (> 6,000 for the most highly exposed group, aerial mixer 
loader) and that EPA believes that short- and intermediate-term 
aggregate risk is likely to be below EPA's level of concern.
    Therefore, BASF believes that the proposed use of bentazon in 
succulent peas in this petition also will not exceed the EPA's level of 
concern for short- and intermediate exposure, since this use is 
identical to the section 18 use of Bentazon. BASF also believes that 
there will be no impact on short- and intermediate-term exposure as a 
result of the use of bentazon in flax since flax is a minor 
agricultural use with no flax product consumed by man as food.

D. Cumulative Effects

    BASF has considered the potential for cumulative effects of 
bentazon and other substances that have a common mechanism of toxicity. 
BASF is unaware of any data indicating that some other active 
ingredient produces toxic effects by a mechanism similar to that of 
bentazon and that would result in cumulative toxicity. Thus, BASF is 
considering only the potential risks of bentazon.

E. Safety Determination

    1. U.S. population-- i. Acute risk. In the final rule establishing 
a time-limited tolerance for bentazon and its metabolites in/on 
succulent peas, EPA performed an acute dietary risk assessment and 
selected the NOEL of 100 (mg/kg/day), based on developmental effects of 
increased postimplantation loss and decreased fetal body weight at the 
LOEL of 250 mg/kg/day, from the developmental toxicity study in rats. 
EPA used tolerance level residues and assumed 100% crop-treated. EPA 
has identified women of child bearing age (females 13+ years old) as 
the most sensitive subpopulation. The resulting high-end exposure 
estimate of 0.01125 mg/kg/day, results in a dietary (food only) MOE of 
8,888 for females 13+ years old which EPA considered acceptable. EPA 
used available monitoring data for groundwater to calculate a water 
exposure estimate of 3 x 10-3 mg/kg/day for adults. Adding this water 
exposure to the food exposure resulted in a MOE of 7,000 for females 
13+ years.
    In the final rule establishing a time-limited tolerance for 
bentazon and its metabolites in/on succulent peas the following items 
are noted: (a) the acute drinking water component of the risk 
calculations presented are relevant to subpopulations with high-end 
exposure within the United States (FL and CA); (b) because the 
calculated risk, based on high-end exposure is acceptable, the overall 
risk assessment is protective of the whole U.S. population; and (c) in 
the best scientific judgment of the Office of Pesticide Programs, the 
aggregate acute risk (food and water) from the currently registered 
uses and section 18 (succulent peas) use of bentazon does not exceed 
EPA's level of concern.
    Therefore, BASF believes that the proposed use of bentazon in 
succulent peas in this petition also will not exceed the EPA's level of 
concern for acute exposure, since this use is identical to the section 
18 use of bentazon. BASF also believes that there will be no impact on 
acute exposure as a result of the use of bentazon in flax. No flax 
product is consumed by man as food and therefore the proposed tolerance 
will not impact the MOE. Furthermore, flax is considered a minor crop 
with <100,000 acres harvested in the US in 1996. Therefore, BASF 
believes that the impact on groundwater exposure will be negligible as 
a result of bentazon use in flax and should not impact the MOE.
    ii. Short- and intermediate-term risk. In the final rule 
establishing a time-limited tolerance for bentazon and its metabolites 
in/on succulent peas, EPA discussed short- and intermediate-term 
exposure. According to EPA, short- and intermediate-term aggregate 
exposure takes into account chronic dietary food and water (considered 
to be a background exposure level) plus indoor and outdoor residential 
exposure. Although residential exposure data are not available for 
ornamentals and ornamental turf uses of bentazon, EPA noted that large 
MOEs were calculated for acute aggregate risk (>= 7,000) and 
occupational exposure (> 6,000 for the most highly exposed group, 
aerial mixer loader) and that EPA believes that short- and 
intermediate-term aggregate risk is likely to be below EPA's level of 
concern.
    Therefore, BASF believes that the proposed use of bentazon in 
succulent peas in this petition also will not exceed the EPA's level of 
concern for short- and intermediate exposure, since this use is 
identical to the section 18 use of Bentazon. BASF also believes that 
there will be no impact on short- and intermediate-term exposure as a 
result of the use of bentazon in flax since flax is a minor 
agricultural use with no flax product consumed by man as food.
    iii. Chronic risk. Using the conservative TMRC exposure

[[Page 43941]]

assumptions described above, BASF has concluded that aggregate exposure 
to bentazon from food will utilize 5.8% of the RfD for the U.S. 
population. The major identifiable subgroup with the highest aggregate 
exposure is non-nursing infants which is discussed below. EPA generally 
has no concern for exposure 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. 
Despite the potential for exposure to bentazon, including all 
anticipated dietary exposure and all other non-occupational exposure, 
BASF does not expect the aggregate exposure to exceed 100% of the RfD. 
BASF concludes that there is a reasonable certainty that no harm will 
result from aggregate exposure to bentazon residues.
    iv. Cancer risk. Bentazon was classified as a ``Group E'' 
carcinogen, which denotes evidence of non-carcinogenicity for humans, 
by the Agency's Health Effects Division Carcinogenicity Peer Review 
Committee, June 26, 1991.
    2. Infants and children-- i. Developmental toxicity testing. 
Developmental toxicity was observed in a developmental toxicity study 
using rats but was not seen in a developmental toxicity study using 
rabbits.
    ii. Developmental toxicity study-- Rat. From the rat developmental 
toxicity study, the maternal (systemic) NOEL was 250 mg/kg/day, the 
HDT. The developmental (fetal) NOEL was 100 mg/kg/day, based on 
increased postimplantation loss and decreased fetal body weight at the 
LOEL of 250 mg/kg/day.
    iii. Developmental toxicity study--Rabbit. From the rabbit 
developmental toxicity study, the maternal (systemic) NOEL was 150 mg/
kg/day, based on abortion and embryonic resorptions at the LOEL of 375 
mg/kg/day. The developmental (fetal) NOEL was 375 mg/kg/day, the HDT.
    iv. Reproductive toxicity study-- Rat. From the rat reproductive 
study, the parental (systemic) NOEL was 62 mg/kg/day, based on 
increased incidences of kidney mineralization and liver microgranules 
at the LOEL of 249 mg/kg/day. The reproductive (pup) NOEL was 15 mg/kg/
day, based on decreased body weight gain at the LOEL of 62 mg/kg/day.
    v. Pre- and post-natal sensitivity. In the rat teratology study, 
fetal effects were observed at the high dose of 250 mg/kg/day in the 
absence of apparent maternal toxicity. However, it should be noted that 
very few general toxicity parameters are investigated for the maternal 
animals in rat teratology studies. Essentially body weight, food 
consumption and clinical signs are all that are determined. Bentazon 
typically does not produce any significant effects on these parameters 
at doses around 250 mg/kg/day. However, other factors indicating 
toxicity to adult animals were observed at a lower dose of 180 mg/kg/
day in the 90-day rat feeding study. These effects consisted of 
increased thromboplastin and prothrombin times, diuresis, clinical 
chemistry changes (e.g. increases in albumin, A/G ratios, and sodium) 
and increased kidney and liver weights. The NOEL in this 90-day rat 
feeding study was determined to be 60 mg/kg/day. A conclusion can be 
drawn that the true NOEL for this study lies between 60 and 180 mg/kg/
day. Since the effects stated above were well defined and characterized 
for the endpoints discussed, the data would suggest that the apparent 
NOEL would be in the range of 80-120 mg/kg/day. Therefore, the maternal 
NOEL and developmental NOEL in the rat study are similar if the same 
parameters are measured in the rat developmental study as are measured 
in the 90-day rat feeding study. Thus, since toxicity to adult animals 
is observed at doses which are similar to or lower than that which 
produced developmental toxicity, it can be concluded that bentazon does 
not produce selective toxicity to fetuses.
    No treatment-related developmental (fetal) toxicity was observed in 
the rabbit teratology study despite testing to a maternally toxic 
level.
    In the rat reproduction study, pup effects were observed at the 
high and mid doses of approximately 249 and 62 mg/kg/day, respectively, 
with parental toxicity observed at the high dose only. However, the 
only effect on offspring at both the mid and high doses was a slight 
decrease in pup weight during the lactation period. These marginal to 
slight differences from control were demonstrated to be transient. The 
F1 pups were kept on the treated diets at the mid and high dose levels 
after lactation. By 4 weeks of age, the F1 pup weights were the same 
for the mid and high doses and control. At the mid dose, there was no 
effect on body weight of the F1 generation animals through 123 days of 
treatment prior to mating.
    In summary, there was no developmental toxicity observed in the 
rabbit teratology study, there was no selective toxicity to fetuses in 
the rat teratology study, and the only effect noted in the reproductive 
toxicity study at a dose below the parental toxicity was a slight and 
transient decrease in pup weight. Based on these results no additional 
safety factor is required for protection of infants and children.
    BASF believes that the RfD used to assess safety to children should 
be the same as that for the general population, 0.03 mg/kg/day. Using 
the conservative exposure assumptions described above, BASF has 
concluded that the most sensitive child population is that of non-
nursing infants (<1- year old). BASF calculates the exposure to 
bentazon residue from all existing tolerances plus the proposed 
increase in tolerance in succulent peas and the tolerance for flax seed 
to be approximately 12.5% of the RfD for non-nursing infants (< 1- year 
old).

F. International Tolerances

    1. Succulent peas. There is a Codex MRL of 0.2 ppm for bentazon and 
its metabolites established in/on garden peas (young pods), a Canadian 
MRL for parent only of 0.1 ppm (negligible) established in/on peas, and 
a Mexican limit for parent (presumed) of 0.05 ppm established in/on 
green peas.
    2. Flax. No maximum residue level (MRL) has been established for 
bentazon in/on flax by the Codex Alimentarius Commission. Austria has 
established a tolerance level for bentazon (including its hydroxy 
metabolites) in/on linseed (seed) of 1.5 ppm. Canada has a maximum 
residue level for parent only of 0.1 ppm in/on linseed. (Joanne I. 
Miller)

2. Novartis Crop Protection, Inc.

PP 8F4955

    EPA has received a pesticide petition (PP 8F4955) from Novartis 
Crop Protection, Inc., PO Box 18300, Greensboro, NC 27419 proposing 
pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act, 
21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance 
for residues of CGA-279202 in or on the raw agricultural commodity on 
pome fruit at 0.4, cucurbit vegetables at 0.25, grapes at 1.5, peanuts 
at 0.02, peanut hay at 4.0, apple pomace at 1.5 and imported bananas at 
0.1 ppm. 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 CGA-279202 in plants 
(cucumbers,

[[Page 43942]]

apples, wheat and peanuts) is well understood. Identified metabolic 
pathways are substantially similar in plants and animals (goat, rat and 
hen). Novartis proposes CGA-279202, per se, as the residue of concern 
for tolerance setting purposes.
    2. Analytical method. Novartis Crop Protection Inc. has submitted 
practical analytical methodology for detecting and measuring levels of 
CGA-279202 in or on raw agricultural commodities. The limit of 
detection (LOD) for each analyte of this method is 0.08 ng injected, 
and the limit of quantitation (LOQ) is 0.02 ppm. The method is based on 
crop specific cleanup procedures and determination by gas 
chromatography with nitrogen-phosphorus detection.
    3 Magnitude of residues--Residue trials. CGA-279202 was applied to 
apples in 10 States and to pears in 4 States for a total of 19 field 
trials. Twelve field trials were conducted in the following 8 
representative peanut-growing States: Alabama, Florida, Georgia, North 
Carolina, Oklahoma, South Carolina, Texas, and Virginia. Eighteen 
cucurbit field trials in 10 States were successfully harvested, 
including 8 cucumber, 5 cantaloupe, and 5 summer squash field trials. 
Twelve field trials in 5 States, accounting for 94% of the U.S. grape 
production, were conducted to generate residue data on grapes, raisins, 
and raw and pasteurized juice. Thirteen banana field trials were 
conducted in Costa Rica, Ecuador, Colombia, Guatemala, Mexico, 
Honduras, and Puerto Rico.

B. Toxicological Profile

    1. Acute toxicity. Studies conducted with the technical material of 
CGA-279202 include a rat acute oral toxicity study with a 
LD50 >5,000 mg/kg; a mouse acute oral toxicity study with a 
LD50 >5,000 mg/kg; a rabbit acute dermal toxicity study with 
a LD50 >2,000 mg/kg; a rat acute dermal toxicity study with 
a LD50 >2,000 mg/kg; a rat acute inhalation toxicity study 
with a LC50 >4.65 mg/L; a rabbit eye irritation study 
showing slight irritation (Category III); a rabbit dermal irritation 
study showing slight irritation (Category IV); a Guinea pig dermal 
sensitization study with the Buehler's method showing negative 
findings; a Guinea pig dermal sensitization study with the maximization 
method showing some positive findings.
    2. Genotoxicty. No genotoxic activity is expected of CGA-279202 
under in-vivo or physiological conditions. The compound has been tested 
for its potential to induce gene mutation and chromosomal changes in 5 
different test systems. The only positive finding was seen in the in 
vitro test system (Chinese hamster V79 cells) as a slight increase in 
mutant frequency at a very narrow range (250 - 278 g/ml) of 
cytotoxic and precipitating concentrations (compound solubility in 
water was reported to be 0.61 g/ml; precipitate was visually 
noted in culture medium at 150 g/ml). The chemical was found 
to be non-mutagenic in the in vivo system or all other in vitro 
systems. Consequently, the limited gene mutation activity in the V79 
cell line is considered a nonspecific effect under non-physiological in 
vitro conditions and not indicative of a real mutagenic hazard.
    3. Reproductive and developmental toxicity. 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 on CGA-279202 
relative to pre- and post-natal effects for children is complete.
    In assessing the potential for additional sensitivity of infants 
and children to residues of CGA-279202, Novartis considered data from 
teratogenicity studies in the rat and the rabbit and a 2-generation 
reproduction studies in the rat. The teratogenicity studies are 
designed to evaluate adverse effects on the developing embryo as a 
result of chemical exposure during the period of organogenesis. 
Reproduction studies provide information on effects from chemical 
exposure on the reproductive capability of mating animals and systemic 
and developmental toxicity from in-utero exposure.
    In the rat teratology study, reductions in body weight gain (bwtg) 
and food consumption were observed in the dam at 100 mg/kg. No 
teratogenic effects or any other effects were seen on pregnancy or 
fetal parameters except for the increased incidence of enlarged thymus, 
which is a type of variation, at 1,000 mg/kg. The developmental NOEL 
was 100 mg/kg.
    In the rabbit teratology study, body weight loss and dramatically 
reduced food consumption were observed in the dam at 250 mg/
kg. No teratogenic effects or any other effects were seen on pregnancy 
or fetal parameters except for the increase in skeletal anomaly of 
fused sternebrae-3 and -4 at the top dose level of 500 mg/kg. This 
finding is regarded as a marginal effect on skeletal development that 
could have resulted from the 40-65% lower food intake during treatment 
at this dose level. The developmental NOEL was 250 mg/kg.
    In the 2-generation rat reproduction study, bwtg and food 
consumption were decreased at 750 ppm, especially in females 
during lactation. Consequently, the reduced pup weight gain during 
lactation (750 ppm) and the slight delay in eye opening 
(1,500 ppm) are judged to be a secondary effect of maternal toxicity. 
No other fetal effects or any reproductive changes were noted. The low 
developmental NOEL, 50 ppm (5 mg/kg), seen in this study was probably 
due to the lack of intermediate dose levels between 50 and 750 ppm. 
Based on an evaluation of the dose-response relationship for pup weight 
at 750 ppm and 1,500 ppm, the NOEL should have been nearly ten-fold 
higher if such a dose was available.
    Based on all these teratology and reproduction studies, the lowest 
NOEL for developmental toxicity is 5 mg/kg while the lowest NOEL in the 
subchronic and chronic studies is 2.5 mg/kg/day (from the rat chronic 
study). Therefore, no additional sensitivity for infants and children 
to CGA-279202 is suggested by the data base.
    4. Subchronic toxicity. In subchronic studies, several mortality 
related changes were reported for the top dose in dogs (500 mg/kg) and 
rats (800 mg/kg). At these dose levels, excessive toxicity has resulted 
in body weight loss and mortality with the associated and nonspecific 
changes in several organs (such as atrophy in the thymus, pancreas, 
bone marrow, lymph node, and spleen) which are not considered specific 
target organs for the test compound. In the dog, specific effects were 
limited to hepatocellular hypertrophy at 150 mg/kg and 
hyperplasia of the epithelium of the gall bladder at 500 mg/kg. Target 
organ effects in the rat were noted as hepatocellular hypertrophy 
(200 mg/kg) and the related liver weight increase 
(50 mg/kg). In the mouse, target organ effects included 
single cell necrosis (300 mg/kg) and hypertrophy (1,050 mg/
kg) in the liver and extramedullary hematopoiesis (300 mg/
kg) and hemosiderosis in the spleen (1,050 mg/kg).
    In general, definitive target organ toxicity, mostly in the liver, 
was seen at high feeding levels of over 100 mg/kg for an extended 
treatment period. At LOEL, no serious toxicity was observed other than 
mostly non-specific effects including a reduction in body weight and 
food consumption or liver hypertrophy.
    5. Chronic toxicity. The liver appears to be the major primary 
target organ based on the chronic studies conducted in mice, rats, and 
dogs. It was identified as a target organ in both the mouse and

[[Page 43943]]

the dog studies with CGA-279202. However, no liver effect was seen in 
the chronic rat study which produced the lowest NOEL of 2.5 mg/kg based 
on reduced bwtg and food consumption seen at higher dose levels (HDL). 
The compound did not cause any treatment-related increase in general 
tumor incidence, any elevated incidence of rare tumors, or shortened 
time to the development of palpable or rapidly lethal tumors in the 18-
month mouse and the 24-month rat studies. Dosages in both studies were 
sufficient for identifying a cancer risk. In the absence of 
carcinogenicity, Novartis believes that a Reference Dose (RfD) 
rapproach is appropriate for quantitation of human risks.
    6. Animal metabolism. CGA-279202 is moderately absorbed from the 
gastrointestinal tract of rats and is rapidly distributed. Subsequent 
to a single oral dose, the half life of elimination is about 2-days and 
excretion is primarily via bile. CGA-279202 is extensively metabolized 
by the rat into about 35 metabolites, but the primary actions are on 
the methyl ester (hydrolysis into an acid), the methoxyimino group (O-
demethylation), and the methyl side chain (oxidation to a primary 
alcohol). Metabolism is dose dependent as it was almost complete at low 
doses but only about 60% complete at high doses.
    In the goat, elimination of orally administered CGA-279202 is 
primarily via the feces. The major residues were the parent compound 
and the acid metabolite (CGA-321113) plus its conjugates. In the hen, 
CGA-279202 is found as the major compound in tissues and in the 
excreta, but hydroxylation of the trifluormethyl-phenyl moiety and 
other transformations, including methyl ester hydrolysis and 
demethylation of the methoxyimino group, are also seen. In conclusion, 
the major pathways of metabolism in the rat, goat, and hen are the 
same.
    7. Metabolite toxicology. Metabolism of CGA-279202 has been well 
characterized in plants, soil, and animals. In plants and soil, 
photolytically induced isomerization results in a few minor metabolites 
not seen in the rat; however, most of the applied materials remained as 
parent compound as shown in the apple and cucumber studies. All 
quantitatively major plant and/or soil metabolites were also seen in 
the rat. The toxicity of the major acid metabolite, CGA-321113 (formed 
by hydrolysis of the methyl ester), has been evaluated in cultured rat 
hepatocytes and found to be 20-times less cytotoxic than the parent 
compound. Additional toxicity studies were conducted for several minor 
metabolites seen uniquely in plants and/or soil. The studies indicate 
that these metabolites, including CGA-357261, CGA-373466, and NOA-
414412, are not mutagenic to bacteria and are of low acute toxicity 
(LD50 >2,000 mg/kg). In conclusion, the metabolism and 
toxicity profiles support the use of an analytical enforcement method 
that accounts for parent CGA-279202.
    8. Endocrine disruption. CGA-279202 does not belong to a class of 
chemicals known for having adverse effects on the endocrine system. 
Developmental toxicity studies in rats and rabbits and reproduction 
study in rats gave no indication that CGA-279202 might have any effects 
on endocrine function related to development and reproduction. The 
subchronic and chronic studies also showed no evidence of a long-term 
effect related to the endocrine system.

C. Aggregate Exposure

    1. Dietary exposure. For the purposes of assessing the potential 
dietary exposure under the proposed tolerances for the residue of CGA-
279202 and its metabolites, Novartis has estimated aggregate exposure 
based upon the Theoretical Maximum Residue Concentration (TMRC). The 
values range from 0.0031 ppm in milk to 1.5 ppm in grapes and include 
tolerances for various crops; pome fruit - 0.4 ppm for the raw 
agricultural commodities (RAC); cucurbits - 0.25 ppm for the RAC; 
grapes - 1.5 ppm for the RAC; peanuts - 0.02 ppm for the RAC; banana - 
0.1 ppm for the RAC. The TMRC is a ``worst case'' estimate of dietary 
exposure since it assumes 100% of all crops for which tolerances are 
established are treated and that pesticide residues are at the 
tolerance levels, resulting in an overestimate of human exposure.
    2. Food--i. Chronic. The RfD of 0.025 mg/ kg/day is derived from 
the 24-month rat NOEL of 2.5 mg/kg/day. Even under worst-case 
assumptions, dietary exposure analysis for CGA-279202 in the most 
exposed population (non-nursing infants <1-year old) shows the percent 
RfD utilization to be only 18.9%. Although tolerances in meat and milk 
are not required for these uses, anticipated residues in meat and milk 
were also included in this exposure analysis. For average U.S. 
populations (48 States), dietary exposure for CGA-279202 shows a 
minimal utilization of 3.4% of the RfD.
    ii. Acute. For CGA-279202, the appropriate NOEL for acute exposure 
is 2,000 mg/kg/day from the acute oral neurotoxicity study in rats. 
Acute dietary exposure analysis predicted the general population will 
be exposed to less than 0.0045 mg/kg/day of CGA-279202, which 
corresponds to a MOE of 44,237 at the 99.9 percentile. Children 1-6 
years constitute the sub-population with the highest predicted 
exposure. Predicted acute exposure for this subgroup is less than 0.026 
mg/kg/day, corresponding to a MOE of at least 7,797 for 99.9% of the 
individuals.
    3. Drinking water. The potential for exposure to CGA-279202 through 
drinking water (surface or ground water) is low; this is due to the 
strong binding affinity of CGA-279202 to soil and to its low use rates 
(0.04-0.125 lb ai/acre/application). The highest average (56-days) 
surface water concentration due to runoff predicted by the GENEEC model 
is 0.06 ppb, resulting from application on turf. Assuming a daily water 
consumption rate of 2 L/day for an adult (70 kg), this would lead to an 
adult intake of 0.0000017 mg/kg/day which is only 0.007% of the chronic 
reference dose of 0.025 mg/kg/day. Assuming a three-fold increase in 
water consumption per unit body weight for children, the potential 
exposure increases only to 0.02% of RfD for this population subgroup. 
Estimated concentrations for treating other crops or for ground water 
are even lower and do not indicate any cause for concern.
    4. Non-dietary exposure. Non-dietary exposure to CGA-279202 is 
considered negligible as the chemical is intended primarily for 
commercial and agricultural use. Exposure due to professional use on 
turf is considered negligible. For workers handling this chemical, 
acceptable margins of exposure (in the range of thousands) have been 
obtained for both acute and chronic scenarios.

D. Cumulative Effects

    Consideration of a common mechanism of toxicity is not appropriate 
at this time since there is no information to indicate that toxic 
effects produced by CGA-279202 would be cumulative with those of any 
other types of chemicals. Furthermore, the oximinoacetate is a new type 
of fungicide and no compound in this general chemical class currently 
has a significant market share. Consequently, Novartis is considering 
only the potential exposure to CGA-279202 in its aggregate risk 
assessment.

E. Safety Determination

    1. U.S. population. Using the conservative exposure assumptions 
described above and based on the completeness and reliability of the 
toxicity data base for CGA-279202,

[[Page 43944]]

Novartis has calculated aggregate exposure levels for this chemical. 
The calculation shows that only 3.4% of the RfD will be utilized for 
the U.S. population based on chronic toxicity endpoints. 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. 
Novartis concludes that there is a reasonable certainty that no harm 
will result from aggregate exposure to CGA-279202 residue.
    2. Infants and children. Developmental toxicity, manifested as 
reduced weaning pup weight, enlarged thymus, or fused sternabrae, was 
observed in the teratology study and 2-generation rat reproduction 
studies at maternally toxic doses. All of these findings are judged to 
be non-specific, secondary effects of maternal toxicity. The lowest 
NOEL for developmental toxicity was established in the rat reproduction 
study at 5 mg/kg, a level that is likely to be an overly low estimate 
(as a result of dose gap) but is still higher than the chronic NOEL of 
2.5 mg/kg on which the RfD is based. Using the same conservative 
exposure assumptions as employed for the determination in the general 
population, Novartis has calculated that the percent of the RfD that 
will be utilized by aggregate exposure to residues of CGA-279202 is 
only 19% for non-nursing infants less than 1-year old (the most 
impacted sub-population). Therefore, based on the completeness and 
reliability of the toxicity data base and the conservative exposure 
assessment, Novartis concludes that there is a reasonable certainty 
that no harm will result to infants and children from aggregate 
exposure to CGA-279202 residues.

F. International Tolerances

    No Codex MRLs have been established for residues of CGA-279202. 
(Janet Whitehurst).
[FR Doc. 98-22012 Filed 8-14-98; 8:45 am]
BILLING CODE 6560-50-F