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EPA BIOPESTICIDES AND POLLUTI ON PREVENTION DIVISION

COMPANY NOTICE OF FILING FOR PE STICIDE PETITIONS PUBLISHED IN

THE FEDERAL REGISTER

EPA Biopesticides and Pollution Prevention Division contact: [insert name and telephone number with area code]

INSTRUCTIONS: Please utilize this outline in p reparing the pesticide petition. In

cases where the outline element does not apply, please insert “NA-Remove” and

maintain the outline. Please do not chan ge the margins, font, or format in your pesticide petition. Simply replace the instructions that appear in green , i.e., “ [insert company name] ,” with the information specific to your action.

SUBMISSION: E-mail the completed temp late to: hollis.linda@epa.gov.

TEMPLATE:

[D-I-1-4, Inc. a division of 1,4Group, Inc.]

[Insert petition number]

EPA has received a pesticide petition ([insert petition number]) from [D-I-1-4, Inc. a division of 1,4Group, Inc.], [P.O. Box 680, Meridian, ID 83680] requesting, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 to establish an ame ndment of an existing tolerance exemption for the biochemical pesticide [1,4-Dimethylnaphthalene (1,4- DMN)].

Pursuant to section 408(d)(2)( A)(i) of FFDCA, as amended, [D-I-1-4, Inc. a division of 1,4Group, Inc.] has submitted the following summary of information, data, and arguments in support of their pesticide petition. This summary was prepared by [D-I-1-4, Inc. a division of 1,4Group, Inc.] and EPA has not fully evaluated the merits of the pesticide petition. The summary may have been edited by EPA if the terminology used was unclear, the summary contained extraneous material, or the summary unintentionally made the reader conclude that the findings reflected EPA’s position and not the position of the petitioner.

I. [D-I-1-4, Inc. a division of 1,4Group, Inc.] Petition Summary

[Insert petition number]

A. Product Name and Proposed Use Practices2

[ Application as a plant growth regulator to inhibit sprouting of potatoes and other sprouting root, tuber and bul b crops during storage and shipping. 1,4-DMN is applied at low levels (2.5 ppm) during the storage season or during shi pping to inhibit sprouting. Application of the product will not increase levels of 1,4-DMN above levels normally found in potatoes and other sprouting crops.]

B. Product Identity/Chemistry

1. Identity of the pesticide and corresponding residues. [ 1,4-Dimethylnaphthalene (1,4-DMN; DMN); OPP Chemical Code: 55802; CAS No. 571-58-4.

1,4-DMN is a plant growth regulator bel onging to the chemical family of alkylsubstituted naphthalenes. 1,4-DMN occurs in potatoes and other sprouting crops, where it naturally inhibits sprouting. As a pestic ide active ingredient, it is used as a plant growth regulator to inhibit sp routing of potatoes and other sprouting root, tuber and bulb crops during storage and shippi ng. 1,4-DMN is highly volatile and has a low solubility in water, and is expected to de grade rapidly in the environment.

1,4-DMN was first registered with EPA in 1994 and a tolerance exemption established at 40 CFR 180.1142 in February 1995.

With this petition the registrant reque sts the current tole rance exemption be

amended to read:

“ 180.1142 - 1,4-Dimethylnaphthalene exempt ion from the requirement of a

tolerance. An exemption from the requirement of a tolerance is established for residues of the plant growth regulator 1,4-Dimethyl naphthalene when applied post-harvest to potatoes and other sprouting root, tuber and bulb crops in accordance with good agricultural practices.” ]

2. Magnitude of residues at the time of har vest and method used to determine the

residue. [N/A]

3. A statement of why an analytical method of detecting and measuring the levels of the pesticide residue are not needed. [ An analytical method for residues is not applicable. It is expected that, when us ed as proposed, 1,4-Dimethylnaphthalene would

not result in residues that ar e of toxicological concern.]

C. Mammalian Toxicological Profile

[ Data on file in support of the current exemption at 40 CFR 180.1142 and

reviewed in that final rule include:

- Acute Oral Toxicity study (rat); LD 50 of 2,730 mg/kg (MRID No. 430825-10). - Acute Dermal Toxicity study (rabbit); LD 50 >2,000 mg/kg ( MRID No. 430825- 11).3

- Acute Inhalation Toxicity study (rat); LC 50 >4.16 mg/L (MRID No. 430825-12). - Primary Eye Irritation st udy (rabbit); moderate irri tant (MRID No. 430825-13). - Primary Dermal Irritation study (rabb it); moderate irritant (MRID No. 430825- 14). - Dermal Sensitization study (guinea pi g); not a sensitizer (MRID No. 430825-15). - Mutagenicity, Ames Test; negative (MRID No. 430825-16). - Mutagenicity, in vitro test for unsch eduled DNA synthesis; negative (MRID No. 430825-17). - Mutagenicity, in vivo micronucleus assay; negative (MRID No. 430825-18).

EPA determined that 1,4-DMN is of low acute toxicity by the oral, dermal and inhalation routes. It is slightly irritating to eyes and mildly irritating to skin, and is not a skin

sensitizer.

Other data on file at the Agency include:

- Subchronic 90-Day Oral Toxicity study (rat). 1,4-DMN was administered to groups of 10 male and 10 female Sprague-D awley rats for 90 days, in the diet, at concentrations of 0, 500, 2500, or 10,000 ppm. An additional 10 rats/sex were included in the control and high-dose gr oups and were held for an additional 28 days to evaluate the recovery potenti al from 1,4-DMN-induced effects. In addition to standard evaluations (such as body weights, clinical pathology, organ weights and histopathology), each rat wa s used to evaluate for potential neurotoxic effects of 1,4-DMN in a f unctional observationa l battery and an automated motor activity assessment, both performed during the 11 th week of

treatment.

Average daily intake of 1,4-DMN was 36, 174, and 713 mg/kg/day for animals in the low, mid and high dose groups, respec tively. No treatment-related deaths occurred during the study. Tr eatment-related clinical si gns were noted mostly in high-dose males and consisted primarily of discolored inguinal fur. No treatmentrelated differences were detected in the functional observationa l battery or motor activity assessments, indicating ,1,4-DMN doe s not express neurotoxic activity. Food consumption was significantly decr eased in the high-dose group, which resulted in reduced body weights. Clinic al pathology profiles did not reveal any biologically-relevant alterati ons. Select organ and organ- to-body or organ-to-brain weight ratios in the high and mid-dose gr oups were significantly different from controls, in most instan ces due to reduced body weights. Liver weight was increased in some mid and high dose fe males but there was no histopathological correlate. Histopathological findings indi cated that the kidn ey was the target organ for 1,4-DMN. Chronic progressive nephropathy (CPN), ba sophilic tubules

and mononuclear cell infiltration were obs erved. CPN was predominately noted in the high-dose males, and the precursory basophilic tubules and mononuclear cells were seen in the 161 mg/kg/day males. The incidence of kidney effects was greater in males than females. After the recovery period, the kidney effects persisted in 6 of 10 high-dose males.4

The NOAEL for 1,4-DMN in rats is 32 mg/kg/day (500 ppm), based on the effect in the kidney of male animals at the next higher dose level, 2500 ppm (161 mg/kg/day) ( MRID No. 463168-06 ).

New data submitted in support of this petition to amend the tolerance include:

- Dermal Sensitization (Local Lymph Node Assay). To determine whether 1,4- DMN causes contact hypersensitivity, three groups of female mice received either 25, 50, or 100% solutions of the test substance applied to the dorsal surface of both ears daily for three consecutive days . Another group was similarly treated with the vehicle, an acetone olive oil mixture. Three days after the last application of 1,4-DMN, the animals rece ived tritiated methyl thymidine after which the lymph nodes were removed fr om each animal. DNA was collected from the lymph node cells and the amount of tritiated methyl thymidine incorporated into the DNA was measured. The amount of radioactivity present in the DNA was equated to a Stimulation Index (SI). If the SI is greater than or equal to 3.0, the substance may cause skin sensitization. The SI values calculated for the 25, 50, and 100% 1,4-DMN were 2.1, 2.4, and 2.8, respectively, indicating that 1,4-DMN does not cause contact hypersensitivity.

- Prenatal Developmental Toxicity study (rat). A developmental toxicity study was conducted in which 1,4-DMN was evaluated for teratogenic activity. In this study, 1,4-DMN was administered daily by oral gavage at dose levels of 0, 25, 80, or 250 mg/kg/day to groups of 23 timed-mated female rabbits. Treatment was from gestation day 6 through gestation da y 28, a period that covers implantation, organogenesis, and histogene sis. The pregnant rabb its were sacrificed on gestation day 29. Fetuses obtained from the pregnant animals underwent visceral and skeletal examinations, while half of the fetuses underwent cephalic

examinations. No treatment-related c linical signs were observed during the study. Mean food consumption was signifi cantly reduced in the high dose group which resulted in reductions in body we ight gains. There was no treatmentrelated differences in litter viability, nu mber of implants, number resorptions, and the number of male, female, and total fetuses. No structural alterations were seen during the fetal examinations, indicat ing that 1,4-DMN did not induce fetal malformations. Thus, the NOEL for mate rnal toxicity was 80 mg/kg/day, while the NOEL for developmental t oxicity was 250 mg/kg/day.

- Measurement of Unscheduled DNA Sy nthesis in Rat Liver using an In

Vivo/In Vitro Procedure . 1,4-DMN was evaluated in an in vivo unscheduled DNA synthesis (UDS) test at two dose le vels. The choice of dose levels was

based on the results of a ra nge-finding study. 1,4-DMN wa s prepared in corn oil and administered to rats via oral gavage . Clinical signs and mortality were observed in the rangefin der at 1400 and 2000 mg/kg Therefore, 1000 mg/kg was considered the maximum tolerated dose (MTD) and was administered as the high dose in the definitive study. The second dose was 500 mg/kg. Separate groups of5

four rats each received either the vehi cle control or the two positive controls, 2- acetamidofluorene or dimethylnitrosamine. Livers were collected 2-4 hours or 12-14 hours after dosing, and were dissociated with collagenase. The resulting hepatocytes were exposed to [ 3 H] thymidine. Incorporation of the radiolabeled thymidine into DNA was evaluated by autoradiography and grain counting.

Negative (vehicle) control animals gave a group mean net nuclear grain (NNG)

value of 0.6 or less with no cells in repair. Group mean NNG values were increased by treatment with 2-acetami dofluorene and dimethylnitrosamine to more than 2.3 with at least 13.7 percent of the cells in repair. The vehicle control

NNG value was consistent with both published and historic al control data, and the system was shown to be sensitive to two known DNA damaging agents that require metabolism for their mutagenic activity. Since treatment with 500 or 1000 mg/kg 1,4-DMN did not produce a group mean NNG value greater than 0.6 and since none of the 1,4-DMN treated ce lls were found in repair, the test

substance did not induce unscheduled DNA synthesis. Therefore, the results indicate that 1,4-DMN does not have mutagenic activity.

- In vitro Percutaneous Absorption of 1,4-Dimethylnaphthalene Through

Human Skin Membranes. The percutaneous absorption of 14 C-1,4- dimethylnaphthalene (1,4-DMN) was determined using human skin samples. The samples were derived from the abdomen and/ or breast of six different skin donors directly after surgery. Subcutaneous fat was removed from the skin and the samples were stored at -18oC until use. After thawing, the skin was dermatomed to a thickness of approximately 400 μ m. The skin membranes were placed in 9 mm flow-through automated diffu sion cells and were main tained at 32 ± 1oC. Prior to initiating the stu dy, the integrity of the skin membranes was confirmed using tritiated water. Expos ure duration was 8 hours, with 16 hours post-exposure time. The dose level, 12 μ g/cm 2

, was based on a worst case estimate of the potatoto-skin transfer of l,4-DMN residues dur ing manual handling of treated potatoes. The donor compartment was covered with a charcoal filter to capture volatile radioactivity.

Receptor fluid samples were collected at 1 hour, 2 hours and at 2-hour intervals until 24 hours after applic ation. After an exposure period of 8 hours, the

unabsorbed test substance was removed fr om the application site using a mild soap solution (3 percent Teepol in wate r) and cotton swabs. At 24 hours after application, the diffusion cells were dismantled. Receptor and donor compartments were washed twice with 1.0 ml ethanol. Each skin membrane was tape stripped 15 times or until the epider mis was ruptured us ing Stripping Discs (CuDerm Corporation). Skin membranes were digested in a 1.5 M KOH solution with 20 percent ethanol for approxi mately 24 hours. Radioactivity was determined by liquid scintillation chromatography in receptor fluid, skin membranes, tape strips, skin wash, donor and receptor compartment, and in

charcoal filter.6

The recovery of 14 C-1,4-DMN in one of the six rep licates was low. Therefore, the results from five replicates were used to calculate the mean values. The mean recovery in these 5 replicates was 87.4  16.1 percent. The mean absorption of

14 C-1,4-DMN into the receptor flui d after 24 hours was 0.22 μg/cm 2 , representing 1.83% of the applied dose. The dermal ab sorption of 1,4-DMN in human skin was determined to be 2.5% of the applie d dose, which includes the amount of radiolabel measured in the receptor compartment wash and the amount of

radiolabel retained in the skin.

- Reproductive Toxicity study, one-generation (rat). In an extended onegeneration reproductive toxicity study, 1,4-DMN was administered daily to Sprague-Dawley rats via their di et at doses of 0, 500, 2000, or 7500 ppm. Parental animals were fed the di ets for two weeks prior to mating, during the two-week mating period, and for the fe males, through gestation, lactation, and until necropsy. Body wei ght, body weight gain, food c onsumption, clinical signs of toxicity, incidence of morbidity and mortality, hematology, clinical chemistry, reproductive performance, and many offspr ing parameters were measured and recorded. In addition, sperm count, morphology, and motility was assessed. Immunologic endpoints measur ed include the T-cell dependent antibody response assay, splenic lym phocyte subpopulation analysis, and examination of thymus and spleen. Offs pring continued to be exposed to 1,4-

DMN via lactation and diet. Some were culled while others were chosen for

additional evaluations. Fetal devel opmental endpoints measured include anogenital distance, vagi nal patency, and preputia l separation. Diagnostic pathology was performed on ma ny organs and tissues.

There were no treatment-related deaths or clinical signs of toxicity. Mean food consumption in the high dose animals wa s significantly reduced, most probably due to palatability of the 1,4-DMN in the diet. This resulted in reductions in body weights and body weight gains in the hi gh dose group. Treatment with 1,4-DMN did not adversely affect reproductive perf ormance, litter viability, or offspring survival. There was no evidence of immunotoxicity. While treatment with 1,4- DMN caused an increase in liver weights in the high dose animals, there were no histological changes in the liver that s uggested heptotoxicity. Thus, the increase in liver weights was determined to be an adaptive response such as enzyme induction. The NOAEL for reproductive toxi city in rats was shown to be 7500

ppm.

- Combined Chronic Toxicity / Carcinogenicity study (rat). D-I-1-4, Inc. conducted a combined chronic toxicity/car cinogenicity study in which SpragueDawley rats received daily oral doses of 1,4-DMN in their diets at 0, 150, 500, or 3750 ppm, equivalent to 0, 10, 33, or 250 mg/kg/day. Animals assigned to the chronic toxicity phase received the test substance for 52 weeks while the animals in the carcinogenicity phase received 1,4-DMN for up to 104 weeks. Ingestion of the high dose of 250 mg/kg/day resulted in decreased food consumption with concurrent decreases in body weight and body weight gain. There were no7

treatment-related mortalities an d no treatment-related effects on hematology, urinalysis, organ weights, or gross pathology. High dose male rats showed minimal to moderate histologic ch anges in the kidney, as did the high dose and mid dose females. Thus the NOEL for chronic toxicity was shown to be 33 mg/kg/day for males and 10 mg/kg/day fo r females. Neoplasms found in this study were typical of those observed inaging rats. There was no treatmentrelated increase in the incidence of a ny type of neoplasm. Therefore, the administration of 1,4-DMN to male and female Sprague-Dawley rats did not cause carcinogenicity. The study wa s conducted in compliance with EPA Guideline 870.4300 and OECD Guideline 453.]

D. Aggregate Exposure

1. Dietary exposure.

i. Food. [ Dietary exposure from use of 1,4-DMN, as proposed, is minimal. The intended use of 1,4-DMN is indoor application to post-harvest crops and it is applied at very low rates below naturally occurring levels. 1,4- DMN is not considered persistent base d on its characteristics, properties or known degradation pathways.

Acute toxicity studies have shown that 1,4-DMN is not toxic during acute,

subchronic and chronic studies. Furt her, 1,4-DMN is not mutagenic as demonstrated in multiple studies. The results of toxicity testing and the lack of anticipated residues on treated commodities show there is no risk to human health from 1,4-DMN. Dietary exposures would not be expected to pose any quantifiable risk due to a lack of residues of toxicological concern. ]

ii. Drinking water. [ Similarly, exposure to humans from residues of 1,4- DMN in consumed drinking water woul d be unlikely. Potential exposure to surface water would be negligible and exposure to drinking water (well or ground water) would be impossible to measure. The intended use of 1,4-DMN is indoor application to post- harvest crops. The ingredient is not applied directly to water.

Acute toxicity studies have shown that 1,4-DMN is not toxic during acute,

subchronic and chronic studies. Furt her, 1,4-DMN is not mutagenic as demonstrated in multiple studies. The results of toxicity testing and the

lack of residues on treated commodities show there is no risk to human health from 1,4-DMN. Drinking water e xposures would not be expected to pose any quantifiable risk due to a lack of residues of toxicological

concern. ]

2. Non-dietary exposure

. [ The potential for non-dietar y exposure to the general population, including infants and children, is unlikely as the proposed use sites are indoor and agricultural. The intended use of 1,4-DMN is application to post-8

harvest crops. 1,4-DMN is not considered persistent based on its characteristics, properties or known degradation pathways.

Acute toxicity studies have shown that 1,4-DMN is not toxic during acute,

subchronic and chronic studies. Furt her, 1,4-DMN is not mutagenic as demonstrated in multiple studies. The resu lts of toxicity testing and the lack of

residues on treated commodities show there is no risk to human health from 1,4- DMN. Non-dietary exposures would not be expected to pose any quantifiable risk

due to a lack of residues of toxicological concern.]

E. Cumulative Effects

[ It is not expected that, wh en used as proposed, 1,4-DM N would result in residues that are of toxicological concern. The in tended use of 1,4-DMN is application to post harvest crops. 1,4-DMN is not considered persistent based on its characteristics, properties or known degradation pathways.

Acute toxicity studies have shown that 1,4- DMN is not toxic duri ng acute, subchronic and chronic studies. Further, 1,4-DMN is not mutagenic as demonstrated in multiple

studies. The results of toxic ity testing and the lack of residues on treated commodities

show there is no risk to human health from 1,4-DMN.]

F. Safety Determination

1. U.S. population. [ The results of toxicity testi ng and the lack of residues on treated commodities show there is no risk to human health from 1,4-DMN. The intended use of 1,4-DMN is application to post-harvest crops. There is a reasonable certainty of no harm to the general US population from exposure to this active ingredient.]

2. Infants and children

. [As mentioned above, it is no t expected that, when used as proposed, 1,4-DMN would result in resi dues that are of toxicological concern. There is a reasonable certainty of no harm for infants and children from exposure to 1,4-DMN from the proposed uses. ]

G. Effects on the Immune and Endocrine Systems

[To date there is no evidence to sugge st that 1,4-DMN functions in a manner similar to any known hormone, or that it acts as an endocrine disrupter.]

H. Existing Tolerances

[There is current a tolerance exemption established, as follows:9

“40 CFR 180.1142. An exemption from the requirement of a tolerance is established for residues of the plant gr owth regulator 1,4-DMN when applied post-harvest to potatoes in accordance with good agricultural practices.” (February 8, 1995)]

I. International Tolerances

[A Codex Alimentarium Commission Ma ximum Residue Level (MRL) is not required for 1,4-Dimethylnaphthalene.]