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propamocarb hydrochloride (Tattoo) Pesticide Tolerance Petition Filing 2/97

[Federal Register: March 12, 1997 (Volume 62, Number 48)]
[Notices]
[Page 11433-11437]
>From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr12mr97-95]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-716; FRL-5589-7]

AgrEvo USA Company; Pesticide Tolerance Petition Filing

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice of filing.
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SUMMARY: This notice announces the filing of a pesticide petition proposing 
regulations establishing tolerances for residues of propamocarb (propyl-3-
[dimethyl-amino] propylcarbamate) hydrochloride (hereafter referred to as 
propamocarb) and its metabolites in or on potatoes and their derived 
commodities, as well as secondary tolerances in meat and milk. This notice 
includes a summary of the petition that was prepared by the petitioner, AgrEvo 
USA Company.

DATES: Comments, identified by the docket control number [PF-716], must be 
received on or before April 11, 1997.

ADDRESSES: By mail, submit written comments to Public Response and Program 
Resources Branch, Field Operations Division (7506C), Office of Pesticide 
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 22202. Comments and data may also be submitted 
electronically be sending electronic mail (e-mail) to: opp-
docket@epamail.epa.gov. Electronic comments must be submitted as an ASCII file 
avoiding the use of special characters and any form of encryption. Comments 
and data will also be accepted on disks in WordPerfect 5.1 file format or in 
ASCII file format. All comments and data in electronic form must be identified 
by docket control number [PF-716]. Electronic comments on this notice may be 
filed online at many Federal Depository Libraries. Additional information on 
electronic submissions can be found below this document.

Information submitted as a comments 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: By Mail, Connie Welch, Product Manager (PM) 
21, 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: Rm 227, Crystal Mall #2, 1921 Jefferson 
Davis Hwy., Arlington, VA 22202, (703) 305-6226; e-mail: 
welch.connie@epamail.epa.gov.

SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition (PP) 6F4707 
from AgrEvo USA Company, Little Falls Centre One, 2711 Centerville Rd., 
Wilmington, DE 19808. The petition proposes, pursuant to section 408 of the 
Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a, to amend 40 CFR 
part 180 by establishing tolerances for the Propamocarb in or on potatoes at 
0.5 part per million (ppm). EPA has determined that the petition contains data 
or information regarding the elements set forth in section 408(d)(2); however, 
EPA has not fully evaluated the sufficieny of the submitted data at this time 
or whether the data support granting of the petition. Additional data may be 
needed before EPA rules on the petition.

As required by section 408(d) of the FFDCA, as recently amended by the Food 
Quality Protection Act, AgrEvo included in the petition a summary of the 
petition and authorization for the summary to be published in the Federal 
Register in a notice of receipt of the petition. The summary represents the 
views of AgrEvo; EPA, as mentioned above, is in the process of evaluating the 
petition. As required by section 408(d)(3) EPA is including the summary as a 
part of this notice of filing. EPA may have made minor edits to the summary 
for the purpose of clarity.

I. Petition Summary

A. Propamacarb Uses

Propamocarb is a specific pesticide with specific activity against several 
Oomycete species which cause seed, seedling, root and stem rots and foliar 
diseases in many edible crops and ornamental plants. The mode of action of 
propamocarb is different compared to other Oomycete fungicides, which provides 
for efficacy against strains that have developed resistance to other 
fungicides. 

B. Metabolism and Analytical Method

1. Analytical method. A practical analytical method utilizing gas/liquid 
chromatography and N-FID or MSD is available and has been validated for 
detecting and measuring levels of propamocarb in or on food. The limit of 
quantification (LOQ) is 0.05 mg/kg (ppm).

2. Metabolism. The absorption, distribution, metabolism and excretion of 
propamocarb has been evaluated in rats. Propamocarb is rapidly absorbed, 
extensively metabolized and rapidly eliminated, primarily via the urine, 
following oral administration. Metabolite profiles were similar following 
single and repeated oral dosing and following intravenous dosing. The primary 
route of metabolism is oxidative degradation with hydrolytic cleavage 
occurring as a secondary pathway.

C. Residues in Plants and Animals

1. Nature and magnitude of the residue in plants. The fate of propamocarb in 
plants is clearly understood. Metabolism studies in cucumbers, potatoes and 
spinach demonstrated that propamocarb is degraded into carbon dioxide which is 
reincorporated into natural plant constituents. The primary residue found in 
all crops, and the only residue of concern, is the parent, propamocarb 
hydrochloride.

More than 50 residue trials on potatoes have been conducted throughout the 
world. The results from these studies indicated that residues of propamocarb 
in raw potatoes from foliar applications were below the LOQ, even when applied 
at 2.5-times the maximum proposed label rate of 4.5 lb ai/A. No measurable 
residues of propamocarb were detected in any of the processed commodities 
following treatment at 2.5-times the maximum proposed label rate and a shorter 
than proposed pre-harvest interval (3 days vs. the proposed 14 days). An 
additional processing study at 5-times the proposed label rate (22.5 lb 
a.i./acre) is now underway. Based on these results, tolerances are proposed 
for the residues of propamocarb in or on potato at 0.5 ppm.

Six residue trials have been conducted on tomatoes, either in the greenhouse 
or in arid climates where no rainfall likely occurred. Based on these data, 
AgrEvo USA expects that residues in tomatoes would not exceed 0.3 ppm when 
used as proposed. Typical residues are anticipated to be significantly lower.

2. Nature and magnitude of the residue in animals. Data are not yet available 
on the metabolism of propamocarb in livestock. A cow metabolism study was 
initiated in September, 1996, and will be submitted to the Agency during 1997. 
However, in a rat metabolism study, propamocarb was extensively degraded and 
rapidly excreted, with >90 percent excreted in the urine within 24 hours. 
Therefore, AgrEvo believes that the potential for residues to occur in animal 
commodities from ingestion of potato processing wastes which contain 
propamocarb residues at or below 0.05 ppm is negligible.

C. Toxicological Profile

The toxicity of propamocarb has been evaluated by EPA as part of previous 
regulatory actions and is summarized below. The conclusions presented are 
those determined by the Agency as reported by the registrant.

1. Acute toxicity. There are no acute toxicity concerns with propamocarb. The 
acute rat oral LD<INF>50 was 2,900 mg/kg in males and 2,000 mg/kg in females. 
The acute rat dermal LD<INF>50 was <ls-thn-eq>3,000 mg/kg. The acute (4-hour) 
inhalation LC<INF>50 in rats was >7.9 mg/l. Propamocarb was not a skin 
sensitizer in guinea pigs. Based on these results, propamocarb hydrochloride 
was classified as Toxicity Category III for acute oral and dermal toxicity, 
and eye irritation, and Category IV for acute inhalation toxicity and skin 
irritation.

2. Subchronic toxicity. In a 90-day feeding study, propamocarb was 
administered to albino rats at concentrations of 0, 20, 50, 100, and 500/1,000 
ppm in the diet. The only effects noted were slightly reduced food efficiency 
and body weight gains at 1,000 ppm.

In a 90-day feeding study in beagle dogs, propamocarb was administered in the 
diet at concentrations of 0, 50, 100, 500, and 1,000/2,000 ppm. No treatment-
related findings were observed.

A 21-day dermal toxicity study was performed with propamocarb in Sprague-
Dawley rats at dose levels of 0, 100, 500 and 1,000 mg/kg/day, 6 hours per 
day, 5 days per week over a 21-day period. No treatment related effects were 
observed.

A 21-day dermal toxicity study was performed with propamocarb in rabbits at 
dose levels of 0, 150, 525 and 1,500 mg/kg/day, 6 hours per day, 5 days per 
week, over a 21-day period. The No Obsereved Effects Level (NOEL) for this 
study was considered by the Agency to be 150 mg/kg/day based on dose-related 
skin irritation in mid- and high-dose animals and a decrease in weight gain in 
mid-dose females.

3. Chronic toxicity/oncogenicity. A 2-year feeding chronic 
toxicity/carcinogenicity study was performed in Sprague-Dawley rats with 
propamocarb at dietary concentrations of 0, 40, 200 or 1,000 ppm. There was no 
evidence of carcinogenicity or other treatment-related effect except for a 
possible reduction in food intake in female rats at the highest level tested. 
Thus, 1,000 ppm (41 mg/kg/day) was considered to be the NOEL. However, this 
study did not satisfy the Agency's criteria for a Maximum Tolerated Dose 
(MTD). A new study at higher dose levels is now in progress.

A 2-year feeding chronic toxicity/carcinogenicity study was performed in CD-1 
mice with propamocarb at dietary concentrations of 0, 20, 100 and 500 ppm. No 
evidence of carcinogenicity or toxicity was noted at any dose level. Thus, 
1,000 ppm (53 mg/kg/day for males and females, respectively), was considered 
to be the NOEL. However, this study did not meet the Agency's criteria for a 
MTD. A new study at higher dose levels is now in progress.

A 2-year feeding study was performed in beagle dogs with propamocarb at 
dietary concentrations of 0, 1,000, 3,000, 10,000 ppm. Decreased weight gain, 
decreased food efficiency and an increased incidence of acute gastric mucosal 
erosions and/or chronic erosive gastritis were noted in all treated groups. 
Thus, a NOEL for this study was not determined but was considered to be 
slightly lower than the lowest dose level tested (33.3 mg/kg/day).

4. Genotoxicity. No evidence of genotoxicity was observed in a battery of 
studies including Salmonella and E. coli gene mutation assays, 2 mouse 
micronucleus assays, an in vitro mammalian cytogenetic assay using cultured 
human lymphocytes, a yeast mitotic gene conversion assay and a yeast mitotic 
recombination assay.

5. Reproduction and developmental toxicity. In a developmental toxicity study, 
rats were administered propamocarb by gavage at dose levels of 0, 74, 221, 
740, or 2,210 mg/kg/day on gestation days 6-19. The NOEL for maternal toxicity 
was 740 mg/kg/day based on mortality, clinical observations and decreased body 
weight gain at 2,210 mg/kg/ day. The NOEL for developmental toxicity was 221 
mg/kg/day based on increased post-implantation loss, decreased fetal weights 
and increased incidence of minor skeletal anomalies (retarded ossification) at 
740 and/or 2,210 mg/kg/day.

In another developmental toxicity study, rabbits were administered propamocarb 
by gavage at dose levels of 0, 15, 45, 150, 300, or 600 mg/kg/day on gestation 
days 6-18. The NOEL for both maternal toxicity and developmental toxicity was 
150 mg/kg/day, based on decreased maternal body weight gain and increased 
post-implantation loss at 300 mg/kg/day.

A three-generation reproduction study was conducted using rats fed diet 
containing propamocarb at dietary concentrations of 0, 40, 200, and 1,000 ppm 
for 100 days and then continuously through 3 successive generations. No 
treatment-related effects were noted on either the parents or offspring.

6. Neurotoxicity. An acute neurotoxicity study was performed in rats at dose 
levels of 0, 20, 200 and 2,000 mg/kg of propamocarb hydrochloride. The overall 
NOEL for this study was determined to be 200 mg/kg based on decreased weight 
gain, soiled fur and decreased motor activity in males and/or females at 2,000 
mg/kg.

A 90-day neurotoxicity study was conducted in rats at dietary concentrations 
of propamocarb hydrochloride of 0, 200, 2,000 and 20,000 ppm. No evidence of 
neurotoxicity (FOB, motor activity or neuropathology) was observed at any dose 
level. Plasma, red blood cell and brain cholinesterase levels were also not 
affected. The NOEL was determined to be 2,000 ppm (142 mg/kg/day) based on 
decreased weight gain at 20,000 ppm.

7. Endocrine effects. No special studies have been conducted to investigate 
the potential of propamocarb to induce estrogenic or other endocrine effects. 
However, the standard battery of required toxicity studies has been completed. 
These studies include an evaluation of the potential effects on reproduction 
and development, and an evaluation of the pathology of the endocrine organs 
following repeated or long-term exposure. These studies are generally 
considered to be sufficient to detect any endocrine effects yet no such 
effects were detected. Thus, the potential for propamocarb to produce any 
significant endocrine effects is considered to be minimal.

E. Aggregate Exposure

Propamocarb is registered for non-food uses on turf and ornamental plants 
(BANOL Fungicide, EPA Reg. No. 45639-88). As such, non-occupational exposure 
would include exposures resulting from consumption of potential residues in 
food or water, as well as exposure to residues from applications to golf 
courses, commercial and ornamental turf, home lawns, sod farms, and ornamental 
plants. There are no acute toxicity concerns with propamocarb. Thus, only 
chronic exposures are being addressed here.

1. Dietary exposure (food). Potential dietary exposures from food under the 
proposed tolerances and potential emergency use time-limited tolerances were 
estimated using the Exposure 1 software system (TAS, Inc.) and the 1977-78 
USDA consumption data. For the purposes of this assessment, AgrEvo USA has 
made the very conservative assumption that 100 percent of all commodities will 
contain propamocarb residues and that all of those residues will be at the 
proposed tolerance levels. (of: 0.05 ppm in potato tubers (whole RAC), and the 
meat, milk, fat, liver, kidney, and meat by-products of cattle, goats, hogs, 
horses, and sheep; and for future time-limited tolerances supporting section 
18 Emergency Uses, 0.3 ppm in tomatoes (whole RAC); 1.0 ppm in tomato juice, 
puree, and catsup; 3.0 ppm in tomato paste). Thus, this estimate should result 
in a gross overestimation of actual human exposure. Copies of these dietary 
exposure analyses are appended to this document.

2. Dietary exposure (drinking water). The potential for propamocarb to leach 
into groundwater has been assessed in four terrestrial field dissipation 
studies conducted in several states and on various soil types. These studies 
were conducted using rates recommended for application to turf, which are 
approximately 24 lb a.i./acre, six times (6X) higher than the total rate 
recommended for use in potatoes and tomatoes. The degradation of propamocarb 
in these studies was rapid, with half-lives ranging from a low of 6 days to a 
high of 17 days. This compound adsorbs strongly to soil, having a moderately 
high soil adsorption coefficient (Kads) of 5.2 and a Koc of 359 in sandy loam 
soil. The compound did not leach under any of the various climatic test 
conditions, in contrast to it s high solubility in water, and did not exhibit 
mobility in either acidic or alkaline soil types. Based on these environmental 
fate data and the anticipated conditions of use, the potential for movement of 
propamocarb into groundwater is very low, and as such the potential 
contribution of any such residues to the total dietary intake of propamocarb 
will be negligible. No Maximum Contaminant Level or Health Advisory Level for 
residues of propamocarb in drinking water has been established.

3. Non-dietary exposure. As a professional use turf and ornamental fungicide, 
propamocarb is used primarily (>90 percent of use) on golf courses for control 
of Pythium blight (BANOL Fungicide, EPA Reg. No. 45639-88). Some limited use 
of BANOL occurs on ornamental plants produced in greenhouses or containers, 
and to a very limited extent on sod farms or by professional lawn care 
applicators to commercial turf. The product is rarely used on homeowner turf 
due to the fact that the diseases it controls (Pythium, Phytophthora) occurs 
primarily in high fertility, high maintenance turf (e.g. golf courses), not in 
homeowner turf. Thus, although non-dietary exposures have not been quantified, 
AgrEvo USA expects them to be minimal since they will occur primarily to 
golfers who will be wearing shoes and socks and who will not enter previously 
treated areas until after the grass has dried. Furthermore, based on the 
limited frequency of use (no more than three applications per year), these 
non-food uses for propamocarb are not likely to result in potential chronic 
exposure and thus should not be factored into a chronic exposure assessment.

G. Cumulative Effects

The potential for cumulative effects of propamocarb and other substances 
having a common mechanism of toxicity must also be considered. The precise 
mechanism of toxicity for propamocarb is unknown. Although a member of the 
carbamate group of pesticides, propamocarb is not an n-methyl carbamate, and 
demonstrated no inhibitory effects on blood or brain cholinesterase following 
either acute or repeated oral administrations to rats and dogs. In vitro 
studies using rat or dog blood plasma showed very slight cholinesterase 
inhibitory effects only at extremely high dose levels, equivalent to about 
2,200 mg/kg bodyweight. This level is 20,000X the established Reference Dose 
for propamocarb. Thus, AgrEvo USA anticipates no cumulative effects with other 
substances.

H. Safety Determinations

1. U.S. population. The Agency has previously established a Reference Dose 
(RfD) value of 0.11 mg/kg/day for propamocarb based on a LOEL of 1,000 ppm 
(33.3 mg/kg/day) from a 2-year dog chronic toxicity study, applying an 
uncertainty factor of 100 to account for interspecies extrapolation and 
intraspecies variation, plus an additional factor of 3 to account for the lack 
of a NOEL. The FAO/WHO/ JMPR have recommended an Acceptable Daily Intake (ADI) 
of 0.1 mg/kg/ day.

Using the conservative (worst-case) dietary exposure assumptions described 
above in paragraph E. 1., chronic dietary exposure will utilize only 1 percent 
of the RfD for the U.S. population. There is generally no concern for 
exposures below 100 percent of the RfD since it represents the level at or 
below which daily aggregate exposure over a lifetime will not pose appreciable 
risks to human health. Thus, AgrEvo USA concludes that there is a reasonable 
certainty that no harm will result to the U.S. population in general from 
aggregate exposure to propamocarb residues.

2. Infants and children. Data from rat and rabbit developmental toxicity 
studies and rat multigeneration reproduction studies are generally used to 
assess the potential for increased sensitivity of infants and children. 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 reproductive 
and other effects on adults and offspring from pre-natal and post-natal 
exposure to the pesticide.

No treatment-related effects to either parental animals or offspring were 
noted in a three-generation rat reproduction study at dose levels up to 1,000 
ppm (33.3 mg/kg/day). No evidence of teratogenicity was noted in either rat or 
rabbit developmental toxicity studies, even at maternally toxic dose levels. 
Increased post-implantation loss was noted in the rabbit study, but only at 
maternally toxic dose levels. The NOEL for both maternal and developmental 
toxicity in rabbits was 150 mg/kg/day. Decreased fetal weights, increased 
post-implantation loss and retarded ossification were noted in rats, and the 
developmental NOEL of 221 mg/kg/day was lower than the maternal NOEL of 740 
mg/kg/day. However, the Agency has concluded that due to the high dose at 
which fetal toxicity was observed, no definite conclusion can be made 
regarding developmental toxicity in this study.

FFDCA section 408 provides that the Agency may apply an additional safety 
factor for infants and children to account for pre- and post-natal toxicity or 
incompleteness of the database. The toxicology database for propamocarb 
regarding potential pre- and post-natal effects in children is complete 
according to existing Agency data requirements and does not indicate any 
particular developmental or reproductive concerns. Furthermore, the previously 
established RfD of 0.11 mg/kg/day, which is based on a 33.3 mg/kg/day LOEL 
from the 2-year dog feeding study, already provides for a safety factor of 
1,364 relative to the 150 mg/kg/day developmental NOEL from the rat 
developmental toxicity study. Thus, AgrEvo USA considers the existing RfD of 
0.11 mg/kg/day to be appropriate for assessing potential risks to infants and 
children and an additional uncertainty factor is not warranted.

Using the conservative assumptions described above, aggregate exposure to 
propamocarb is expected to utilize 3 percent of the RfD in non-nursing infants 
and 2 percent of the RfD in children aged 1-6. These numbers would be 
significantly lower if anticipated residues were utilized rather than 
tolerance values. Therefore, AgrEvo concludes that there is a reasonable 
certainty that no harm will result to infants or children from aggregate 
exposure to propamocarb residues.

I. International Tolerances

The Codex Alimentarius Commission (Codex) has established tolerances (MRLs) 
for propamocarb in the following raw agricultural commodities:

---------------------------------------------------------------
Commodity                             Part per million
---------------------------------------------------------------
Beetroot                                  0.2 ppm
Brussels sprouts                          1.0 ppm
Cabbage, head                             0.1 ppm
Celery                                    0.2 ppm
Cucumber                                  2.0 ppm
Cauliflower                               0.2 ppm
Lettuce, head                             10.0 ppm
Pepper, sweet                             1.0 ppm
Radish                                    5.0 ppm
Strawberry                                0.1 ppm
Tomato                                    1.0 ppm
---------------------------------------------------------------

The FAO/WHO/JMPR have recommended an Acceptable Daily Intake (ADI) of 0.1 
mg/kg/day.

J. Conclusions

AgrEvo USA believes that the proposed use of propamacarb on potatoes would not 
pose a significant risk to human health, including that of infants and 
children, and is in compliance with the requirements of the Food Quality 
Protection Act of 1996. Moreover, the proposed tolerances for propamocarb in 
potato commodities, meat and milk, of 0.05 ppm, should be established.

II. Public Record

Interested persons are invited to submit comments on this notice of filing. 
Comments must bear a notation indicating the docket control number, [PF-716]. 
All written comments filed in response to this petition will be available in 
the Public Response and Program Resources Branch, at the address given above 
from 8:30 a.m. to 4 p.m., Monday through Friday, except legal holidays.

A record has been established for this notice under docket control number [PF-
716] 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 public record is located in Rm. 1132 of the 
Public Response and Program Resources Branch, Field Operations Division 
(7506C), Office of Pesticide Programs, Environmental Protection Agency, 
Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA.

Electronic comments can be sent directly to EPA at: opp-docket@epamail.epa.gov

Electronic comments must be submitted as ASCII file avoiding the use of 
special characters and any form of encryption.

The official record for this notice, as well as the public version, as 
described above will be kept in paper form. Accordingly, EPA will transfer all 
comments received electronically into printed, paper form as they are received 
and will place the paper copies in the official record which will also include 
all comments submitted directly in writing. The official record is the paper 
record maintained at the address in ``ADDRESSES'' at the beginning of this 
document.

Authority: 21 U.S.C. 346a.

List of Subjects

Environmental protection, Administrative practice and procedure, Agricultural 
commodities, Pesticides and pests, Reporting and recordkeeping.

Dated: February 26, 1997.

Peter Caulkins
Acting Director
Registration Division
Office of Pesticide Programs

[FR Doc. 97-5681 Filed 3-11-97; 8:45 am]