1

Federal Food, Drug, and Cosmetic Act (FFDCA) Considerations for Tobacco mild green mosaic tobamovirus strain U2

Docket ID Number: EPA

- HQ

- OPP

- 201 3

- 0 761

Date: October 30 , 2014

Section 408(c)(2)(A)(i) of FFDCA allows the EPA to establish an exemption from the requirement for a tolerance (the legal limit for a pesticide chemical residue in or on a food) only if the EPA determines that the exemption is “safe.” Section 408(c)(2)(A)(ii) of FFDCA defines “safe” to mean that “th ere is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information.” This includes exposure through d rinking water and in residential settings but does not include occupational exposure. Pursuant to FFDCA section 408( c )(2)(B) , in establishing or maintaining in effect an exemption from the requirement of a tolerance, the EPA must take into account the fact ors set forth in FFDCA section 408(b)(2)(C), which require the EPA to give special consideration to exposure of infants and children to the pesticide chemical residue in establishing a tolerance or tolerance exemption

, and to “ensure that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to th e pesticide chemical residue . . . . ” Additionally, FFDCA section 408(b)(2)(D) requires that the EPA consider “available info rmation concerning the cumulative effects of [a particular pesticide's] . . . residues and other substances that have a common mechanism of toxicity.”

The EPA performs a number of analyses to determine the risks from aggregate exposure to pesticide residue s. First, the EPA determines the toxicity of the pesticide . Second, the EPA examines exposure to the pesticide through fo od, drinking water, and other exposures that occur as a result of pesticide use in residential settings.

I. Summary of Petitioned

- for Tolerance Exemption

In the Federal Register of February 21, 2014 ( 79 FR 9870 )

, the EPA issued a notice pursuant to FFDCA section 408(d)(3)

, 21 U.S.C. 346a(d)(3), announcing the filing of a pesticide tolerance petition (PP 3E8181 ) by Interregional Research Project Number 4 (IR

- 4), 500 College Road East

, Suite 201W

, Princeton, NJ 08540. The petition requested that 40 CFR part 180 be amended by establishing an exempt ion from the requirement of a tolerance for residues of Tobacco mild green mosaic tobamovirus strain U2 . Th at document referenced a summary of the petition prepared by the petitioner IR

- 4 , which is available in D ocket ID Number EPA

- HQ

- OPP

- 201 3

- 0761 via http://www.regulations.gov

.

II

. Toxicological Profile

Consistent with FFDCA section 408(b)(2)(D), the EPA reviewed the available scientific data and other relevant information on Tobacco mild green mosaic tobamovirus strain U2 , and considered its validity, completeness, and reliability, as well as the relationship of this information to human risk. The EPA also considered available information concerning the variability of the sens itivities of major identifiable subgroups of consumers, including infants and children.

A. Overview of Tobacco mild green mosaic tobamovirus strain U2

Tobacco mild green mosaic tobamovirus strain U2 is a tobamovirus, a type of plant virus, and tobamoviru ses have no known toxicity, pathogenicity, or infectivity to any organisms other than plants. They are unable to infect animals because they lack cell surface binding site receptors common to animal viruses. Tobamoviruses enter plant cells only through ope n wounds (e.g., those produced by feeding insects2 or by mechanical methods) or by cell

- to

- cell transfer (Ref. 1). Almost all living things are routinely exposed to plant viruses, including tobamoviruses, through plants and plant products (e.g., foods.). To bacco mild green mosaic tobamovirus strain U2 is known to infect several species of plants, including peppers (Refs. 2 and 3); therefore, humans are likely already exposed to Tobacco mild green mosaic tobamovirus strain U2 through food. Throughout the avai lable literature, there are no reports of adverse effects in animals resulting from ingestion or exposure to Tobacco mild green mosaic tobamovirus strain U2. Tobacco mild green mosaic tobamovirus strain U2 has not been reported to multiply in insects nor i n any other known animal. One reference provided by the petitioner may show replication of Tobacco mosaic virus (another tobamovirus) in cultured, immune

- suppressed, monkey kidney cell lines (Ref. 4); however, this was an artificial system and does not ind icate that plant viruses can normally replicate in animal cells. The specific mode of action of Tobacco mild green mosaic tobamovirus strain U2 is such that only some species within the plant family Solanaceae are lethally susceptible to this virus. Labora tory animals, such as rabbits, mice, chickens, and guinea pigs, are routinely used for producing antibodies against tobamoviruses without causing adverse effects to the animals. In addition, there are no reports of humans that handle and administer the vir uses or of these laboratory animals developing any nasal, eye, skin, or pulmonary allergies, or any other adverse reactions to the viruses.

B. Microbial Pesticide Toxicology Data Requirements

In support of this tolerance exemption and to fulfill the mammalian toxicology requirements, the petitioner submitted scientific rationale and public literature (briefly summarized in S ection II.A above )

. Specifically, the information provided supports the lack of toxicity to mammals and human s to tobamoviruses, that only certain plants (and no animals) are susceptible to Tobacco mild green mosaic tobamovirus strain U2, and that Tobacco mild green mosaic tobamovirus strain U2 poses little to no risk to humans.

1. Acute oral toxicity/pathogeni city (Harmonized Guidel ine 885.3050; MRID Nos. 467416

- 02, 469187

- 01, 479232

- 01, and 480296

- 01 )

. To fulfill this data requirement, the petitioner submitted supporting scientific rationale and public literature that show plant viruses, including Tobacco mild green mosaic tobamovirus strain U2, are found in food ingested daily by humans and animals and that no known adverse effects or deaths have occurred in any species as a result of such dietary exposures. The EPA believes that this information i ndicates that this virus wou ld not be toxic, infective, or pathogenic through the oral route of exposure and , as a result, has waived acute oral toxicity/pathogenicity testing for Tobacco mild green mosaic tobamovirus strain U2 (Refs. 5, 6 , and 7 )

.

2

. A cute pulmonary toxicity/pathogenicity (Harmonized Guideline 885.3150; MRID Nos. 467416

- 02, 469187

- 01, 479232

- 01, and 480296

- 01 )

. To fulfill this data requirement, the petitioner submitted supporting scientific rationale and pub lic literature that show plan t viruses, including Tobacco mild green mosaic tobamovirus strain U2, are ubiquitous in plants and are not known or expected to cause acute pulmonary toxicity, pathogenicity , or infectivity in mammals. Upon consideration of all this information

, the EPA has waived acute pulmonary toxicity/pathogenicity testing for Tobacco mild green mosaic tobamovirus strain U2 (Refs. 5, 6, and 7).

3

. Acute injection toxicity/pathogenicity (Harmonized Guideline 885.3200 ) . Not required because Tobacco mild green mosaic tobamovirus strain U2 is a virus (refer to test note #2 of 40 CFR § 158.2140(d) ).

4

. Hypersensitivity incidents (Harmonized Guideli ne 885.3400; MRID Nos. 467416

- 02, 469187

- 01, 479232

- 01, and 480296

- 01 ) . The petitioner reported that no hypersensitivity incidents, including immediate

- type or delayed

- type reactions of humans and domestic animals, occurred during research, development, or testing of Tobacco mild green mosaic tobamovirus strain U2 (Refs. 5, 6, and 7).3 5. Cell c ulture (Harmonized Guideline 885.3500; MRID Nos. 467416

- 02, 469187

- 01, 479232

- 01, and 480296

- 01 ) . To fulfill this data requirement, the petitioner submitted scientific rationale and supported it with public literature. Tobamoviruses are unable to infect animal cells since the cell surface plays an important role in infection of animal cells; during infection, animal viruses interact specifically with receptor s on the animal cell surface. Plant viruses, on the other hand, lack recognition for these receptors and only enter plant cells through open wounds or via cell

- to

- cell transfer through intercellular connections (Ref. 1). There is one report in the literatu re of growing Tobacco mosaic virus (TMV; a different tobamovirus from the one that is the subject of this tolerance exemption) in cultured, immune

- suppressed, monkey kidney cell lines (Ref. 4); however, this was an artificial system and does not indicate t hat plant viruses can normally replicate in or infect animal cells. Upon consideration of all this information, the EPA has waived cell culture testing for Tobacco mild green mosaic tobamovirus strain U2 (Refs. 5, 6, and 7).

6. Acute dermal toxicity ( Harmonized Guideline 870.1200; MRID No. 480296

- 01 ) and primary dermal irritation (Harmonized Guideline 870.2500; MRID Nos. 469187

- 01, 479232

- 01, and 480296

- 01)

. To fulfill these data requirement s , the petitioner submitted supporting scientific rationale an d public literature that show plant viruses, including Tobacco mild green mosaic tobamovirus strain U2, are ubiquitous in plants and are not known or expected to cause dermal toxicity or irritation in mammals. Upon consideration of all this information, th e EPA has waived acute dermal toxicity and primary dermal irritation testing for Tobacco mild green mosaic tobamovirus strain U2 (Refs. 5, 6, and 7).

III. Aggregate Exposure

In examining aggregate exposure, FFDCA section 408 directs the EPA to consider available information concerning exposures from the pesticide residue in food and all other non

- occupational exposures, including drinking water from ground water or surface water and exposure through pesticide use in gardens, lawns, or buildings (residential and other indoor uses).

Food Exposure : Virus

- infected food plants have always been a part of the human diet and domestic animal food supply (Refs. 8, 9, 10, 11, 12, and 13). Most plants may be infected by at least one virus, and components of plant viruses are often found in the produce of crop plants. Even plants that show no disease symptoms are often found to be infected with viruses (Refs. 12 and 14). In addition, a common agricultural practice used since the 1920s for protection against v iral disease involves intentionally inoculating healthy plants with a mild form of a virus in order to prevent infection by a more virulent form (Ref. 14). A great deal of information supports the ubiquitous appearance of plant viruses in foods and, to dat e, there have been no reports of adverse human or animal health effects associated with consumption of plant viruses in food. Furthermore, applications of Tobacco mild green mosaic tobamovirus strain U2 , which are limited to pastures and wooded areas that are fenced to contain grazing animals

, are not expected to result in increa sed exposures of the active ingredient to the general population. The only residues anticipated on food with this limited use site are on gra ss, grass hay , and nongrass animal feeds (e.g., alfalfa and clover)

. T hese residues on grass

, grass hay , and nongrass animal feeds would be incidental to applications to the target plant (tropical soda apple), given that grass and the nongrass animal feeds are not host s for Tobacco mild green mo saic tobamovirus strain U2 and that Tobacco mild green mosaic tobamovirus strain U2 cannot infect or replicate in grass or in the nongrass animal feeds

. In the remote likelihood that Tobacco mild green mosaic tobamovirus strain U2 is present i n food, suppo rting scientific literature indicate s that no toxicity, pathogenicity, or infectivity is likely to occur with any food exp osure resulting from the use of this microbial herbicide when applied in accordance with label directions and good agricultural practi ces (see additional discussion in Section II of this document ).4 Drinking Water Exposure : Tobacco mild green mosaic tobamovirus strain U2 is not intended for use in drinking water. In the unlikely event that Tobacco mild green mosaic tobamovirus strain U2 reach es water consumed by humans (e.g., through spray drift), for the reasons enumerated previously , the EPA concludes that no toxicity, pathogenicity, or infectivity is likely to occur with any drinking water exp osure resulting from the use of this micro bial herbicide when applied in accordance with label directions and good agricultural practices (see additional discussion in Section II of this document ).

Other Non

- occupational Exposure : D ermal or inhalation exposure to the general popula tion due to use of Tobacco mild green mosaic tobamovirus strain U2 is not likely to occur, based on the limited use site and application methods . Moreover, the general population, including infants and children, are exposed to plant viruses daily in food with no known adv erse effects ever being reported. Therefore, the EPA concludes that

, should there be non

- occupational, non

- dietary exposures to Tobacco mild green mosaic tobamovirus strain U2, such exposure s would pose no risks to the general population, including infants and children.

IV. Cumulative Effects from Substances with a Common Mechanism of Toxicity

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the EPA consider “available information concerning the cumulative effects of [a particular pesticide’s] . . . residues and other substances that have a common mechanism of toxicity.”

The EPA has not found Tobacco mild green mosaic t obamovirus strain U2 to share a common mechanism of toxicity with any other substances, and Tobacco mild green mosaic tobamovirus strain U2 does not appear to produce a toxic metabol ite . For the purposes of this tolerance action, therefore

, the EPA has assumed that Tobacco mild green mosaic tobamovirus strain U2 does not have a common mechanism of toxicity with other substances. Following from this, therefore, the EPA concludes that there are no cumulative effects associated with Tobacco mi ld green mosaic tobamovirus strain U2 that need to be considered. For information regarding the EPA’s efforts to determine chemicals that have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the EPA’s website at http://www.epa.gov/pesticides/cumulative

.

V. Determination of Safety for the U .S. Population, Infants and Children

A. U.S. Population

For all of the reasons discussed previously, there is reaso nable certainty that no harm will result to the U.S. population, including infants and children, from aggregate exposure to residues of Tobacco mild green mosaic tobamovirus strain U2. This includes all anticipated dietary exposures and all other exposures for which there is reliable information.

B

. Infants and Children

FFDCA section 408(b)(2)(C) provides that the EPA shall apply an additional tenfold (10X) margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the database on toxicity and exposure, unless the EPA determines based on reliable data that a different margin of safety will be safe for infants and children. Th is additional margin of safety is commonly referred to as the Food Quality Protection Act Safety Factor. In applying this provision, the EPA either retains the default value of 10X or uses a different additional safety factor when reliable data available t o the EPA support the choice of a different factor. Humans, including infants and children, have been exposed to plant viruses through food, where they are commonly found, with no known or reported5 adverse effects. As discussed ab ove, the EPA has concluded that TMGMV U2 is not toxic, pathogenic, or infective to mammals, including infants and children. Because there are no threshold levels of concern to infants, children, and adults when TMGMV U2 is used according to label directions and good agricultural
pr actices, the EPA concludes that no additional margin of safety is necessary to protect infants and children.

VI . Conclusions

The EPA concludes that there is a reasonable certainty that no harm will result to the U.S. population, including infants and children, from aggregate exposure to residues of Tobacco mild green mosaic tobamovirus strain U2 . Therefore, the existing temporary to lerance exemption for Tobacco mild green mosaic tobamovirus is amended by establishing a permanent exemption from the requirement of a
to lerance for residues of Tobacco mild green mosaic tobamovirus strain U2 in or on all commodities of crop groups 17 and 18 when applied as a post

- emergent herbicide and used in accordance with label directions and good agricultural practices.

VII . References

1. Fraenkel

- Court H, Kimball PC, Levy JA. 1988. Virology, 2 nd edition. Prentice Hall, Englewood Cliffs, NJ (Virus cellular receptors and cell membrane changes, pgs. 299

– 300).

2. Brunt AA, Crabtree K, Dallwitz MJ, Gibbs AJ, Watson L, Zurcher EJ (eds.). 1996. Plant Viruses Online: Descriptions and Lists from the VIDE Database (Tobacco mild green mosaic tobamovirus). Version: 20 th August 1996. Available from http://pvo.bio

- mirror.cn/descr801.htm

.

3. Wetter C. 1989 . Tobacco mild green mosaic virus. In: AAB Descripti on of Plant Viruses No. 351. Available from http://www.dpvweb.net/dpv/showdpv.php?dpvno=351

.

4. Atherton JG. 1968. Formation of tobacco mosaic virus in an animal cell culture. Archiv fur die gesamte Virusforschung 24:406

– 418.

5. U.S. EPA. 2010. SolviNix TM LC Containing Tobacco Mild Green Mosaic Virus, ATCC PV

- 1200. Memorandum from J.V. Gagliardi, Ph.D. through J.L. Kough, Ph.D. to J. Kausch, dated November 9, 2010.

6. U.S. EPA. 2006a. Solvini x Containing TMGMV (Tobacco Mild Green Mosaic Tobamovirus). Memorandum from J.V. Gagliardi, Ph.D. through J.L. Kough, Ph.D. to R. Edelstein, Ph.D., dated May 23, 2006.

7. U.S. EPA. 2006b. Replacement Data Waiver Reviews for Solvinix Containing TMGMV (Toba cco Mild Green Mosaic Tobamovirus). Memorandum from J.V. Gagliardi, Ph.D. through J.L. Kough, Ph.D. to R. Edelstein, Ph.D., dated September 7, 2006.

8. Dewan C, Pearson MN. 1995. Natural field infection of garlic by garlic yellow streak virus in the Puke kohe area of New Zealand and associated problems with the introduction of new garlic cultivars. New Zealand Journal of Crop and Horticultural Science 23:97

– 102.

9. McKinney HH. 1929. Mosaic diseases in the Canary Islands, West Africa, and Gibraltar. Journ al of Agricultural Research 39:557

– 578.6

10. Provvidenti R, Gonsalves D. 1984. Occurrence of zucchini yellow mosaic virus in cucurbits from Connecticut, New York, Florida, and California. Plant Disease 68:443

– 446.

11. Palukaitis P. 1991. Virus

- mediated genetic transfer in plants. In: Levin M, Strauss H. Risk Assessment in Genetic Engineering. New York: McGraw

- Hill, pgs. 140

– 162.

12. Jones L, Anderson E, Burnett G. 1934. The latent virus of potatoes. Journal of Phytopathology 7:93

– 115.

13. Beemster ABR, de Bokx JA. 1987. Survey of properties and symptoms. In: de Bokx JA, van der Want JPH. Viruses of Potatoes and Seed Potato Production. Wageningen: Pudoc, pgs. 84

– 93.

14. Fulton R. 1986. Practices and precautions in the use of cross pro tection for plant virus disease control. Annual Review of Phytopathology 24:67

– 81.