Ka s ugam yci n Human Health Risk Assessment DP Barcode D41 5977

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, DC 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

MEMORAND U M

Date:

Sub ject: 20 November 2013

Kasugamycin. ADDENDUM to the Hum an Health Risk Assessment for the Propo se d Use ofthe Fungicide on Fruiting Vegetabl es, Pome Fruits

, and Walnut s

.

PC Code: 230001 DP Barcode: 0415977 Decision Number: 427886 Registration Numbe r : 66330-404 Petition N umber: OF7689 Regulatory Action: Sec ti on 3 R egist r at ion Risk Assessment Type: Single C hemi cal Ag greg at e Case Number: 7 045 TXR Number: NA CAS Number: 6980-18-3 MRID Numbers : NA 40CFR: §1 80 .614

From : William T. Dr ew , Ch e mist/Ri sk Assessor

# ~ R eg i s tr atio n Action Branch II (RAB2)

Through:

To: Health Eff ects Division (HED)

, 7509P

Chr i stina Swartz, Chi ef RAB2/HED, 7509P

# ~~

S haunta Hill and Hop e John son, RM Team 2 1 Fungicide Bran c h ( FB ) Registrat i on Di v i sion ( RD)

, 7505P

Back!!round: Canada ' s Pe st Management R egu lato ry Agency ( PMRA) has recen tly established maximum residu e limit s (MRLs) for kasugamycin in fruiting vegetables, pome fru i ts, and walnuts that differ from the US toleran ces previously r ecommended by H ED in its lat es t risk
assessment ( 0 37660 8 ; W.T. Drew; 1 3 July 2012). In order to harmoniz e with th e MRL s

es tablish e d by Canada

, H E D has revi sed it s recommended tolerances in fruiting vegetables (g r ou p 8-1 0)

, pome fruits (grou p 11-1 0), and walnuts. Pur su ant to that decision

, this addendum ad dress es HED 's revised t olerance and label r e commendations

, and the resu ltin g changes to the dietary exp osur e and ri s k assessment. All other aspects of the human health ri sk assessment remain unchanged since the 2012 a ssess m ent , and are not r e-it era ted her e in

.

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### 1.0 Executive Summary

Arysta LifeScience North America LLC, as an agent for Hokko Chemical Industry Company Limited (Japan), has proposed the establishment of permanent tolerances for residues ofthe amino glycoside fungicide kasugamycin (3-0-[2-amino-4-[( carboxyimino-methyl)amino ]- 2,3,4,6-tetradeoxy-a-D-arabino-hexopyranosyl]-D-chiro-inositol, CAS #6980-18-3) in or on fruiting vegetables group 8-10, pome fru i ts group 11-10, and walnuts

. The proposal is associated with the first US registration for this active ingredient (ai).

Kasugamycin is a low-use-rate, wide

- spectrum aminoglycos i de antib i otic fungicide produced from Streptomyces kasugaensis. Kasugamycin formulations are applied as foliar sprays in agriculture and horticulture

. Kasugamycin has preventative, curative and sys t emic activity at low application rates

. The compound controls a range of phytopathogenic organisms in the proposed crops

. Kasugamycin is currently used in over 20 countries on different crops including
to ma to, paprika, eggplant, rice and potato

. HED previously recommended in favor of a tolerance for residues ofkasugamycin in i mported fruiting vegetables and a time-limited tolerance for residues in app l es.

Kasugamycin is a member of the aminoglycoside fami l y of antibiotics, which a l so includes streptomycin and gentamicin. These agents inhibit bacterial protein synthes i s by binding to the 30S subunit of the bacterial ribosome. Their penetration through the cell membrane of the bacterium depends partly on oxygen

- dependent active transport by a polyamine carrier system that seems to be absent in mammalian systems. This risk assessment document does not address the potential impact of the pesticidal use ofkasugamycin on ant i biot i c resistance. Tolerance l evels as recommended within this document are presented excluding antib i otic resistance impacts / concerns

.
Toxicology: The toxicology database is complete for kasugamycin, and the available guideline toxicity data are considered adequate for risk assessment purposes. Kasugamycin exhibits low
acute toxicity. The major effects observed across species in multiple-dose studies were decreased body weights and body weight gains

. Testicular atrophy was also observed in the rat reproductive and mouse subchronic toxicity studies, but only at doses significantly higher than the l owest-observed-adverse-effect level (LOAEL) in the rat study, or above the limit do se in the

mouse. There was no evidence that exposure to kasugamycin results in neurotox i city, and a developmental neurotoxicity (DNT) study is not required. A 28-day rat inhalation toxicity study has not been submitted. However
, HED's Hazard and Science Policy Counc il (HASPOC) has determined tha t a repeated exposure inhalation study is not required, based on the available hazard and expo sure info rmation, including the following cons i derat i ons : selection of irritation

as the endpoint of concern for inhalation exposure, based on irritation seen follow in g ora l
exposures i n multip l e studies; the use of an oral no-observed -adverse-effect level (NOAEL) which results in occupational handler margins of exposure (MOEs) ranging from 58,000 to 2,500,000 for risk via the inhalation route; the physicochemical properties, and low vo l at ili ty, of

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### Page 3 of 8 kasugamycin; the low acute inhalation toxicity ( Toxicity Category IV) ; and t he low potential for inhalation exposure , based on the proposed use pattern (TXR # 0052461).

Bec a u se o f kasugamycin ’s toxicological profile, low application rates, low vapor pressure, lack of residential uses, lack of persist ence in the environment, and inhalation MOEs all ≥58,000

, a 10X UF DB 

### is not required for the lack of th e inhalation study.

The database is complete with respect to pre

- and post

- natal toxicity, and shows no evidence of increased qualitative or quantitat ive susceptibility in the offspring, or in the developing fetus. Based on the hazard and exposure data, HED has recommended that the required Food Quality Protection Act (FQPA) 10X safety factor be reduced to 1X. Therefore, uncertainty factors used in th e assessment consist of a 10X factor for interspecies extrapolation, and a 10X factor for intraspecies variability. There was no evidence of carcinogenicity in male and female mice

, n or in male and female rats at doses that were adequate to assess the car cinogenic potential of kasugam y cin. There was no evidence of mutagenicity. Based on the overall weight of the evidence, kasugamycin is classified as "not likely to be carcinogenic to humans”.

There were no toxic effects associated with a single dose o f kasugamycin; therefore, an acute dietary endpoint and dose were not selected for the general US population, or any population subgroup. The dose and endpoint from the rat combined chronic toxicity/carcinogenicity study

w ere selected for chronic dietary exposure and risk assessment. The NOAEL of 11.3 mg/kg/day was based on testicular softening and atrophy at the LOAEL of 116 mg/kg/day. Testicular atrophy is consistent with findings of other studies

. There was no systemic toxicity associated with dermal exposure in an acceptable dermal toxicity study in the rat, and therefore a dermal endpoint and dose were not selected. For inhalation exposure (short

- and intermediate

- term), the dog subchronic and rabbit developmental toxicity studies were selected as co

- critical studies. The endpoint of concern is irritation since kasugamycin appears to be irritating to the oral and gas trointestinal tract mucosa following oral
exposures. In the subchronic study with dogs, irritation o f the oral cavity was characterized as tongue lesions, swollen mouth, excessive salivation, and thickening of the skin at the commissures of the mouth. Th e NOAEL was 11 mg/kg/day

, and the LOAEL was 106 mg/kg/day. The developmental rabbit study was selected as the co

- critical study since the maternal NOAEL (10 mg/kg/day) was comparable to the NOAEL in the dog study

, and the maternal toxicity may have manife sted due to the irritation potential of the compound. T he use of the oral NOAEL results in MOEs ranging from 58,000 to 2,500,000 for risk from occupational exposure via the inhalation route.

Residue Chemistry: The nature of kasugamycin residues in plan ts and livestock (ruminants) is adequately understood. The residue of concern for tolerance enforcement and risk assessment is the parent compound, although no tolerances are needed in livestock commodities based on the proposed uses. The parent kasugamy cin and 2 degradates with similar mobility were recommended for inclusion in the drinking water modeling. Adequate residue data wereKasugamycin Human Health Risk Assessment DP Barcode D 4 15977



### Page 4 of 8 submitted to support the proposed uses on fruiting vegetables group 8

- 10, pome fruits group 11

- 10 , and walnuts. HED has u sed conservative assumptions to assess the risk from chronic dietary exposure to kasugamycin through food and drinking water. These include the use of recommended tolerance

- level residues, modeled drinking water estimates, and the assumption that all requ ested commodities are treated, or 100% crop treated (CT). Chronic dietary risk estimates for kasugamycin are below HED’s level of concern (LOC) of 100% of the chronic population adjusted dose (cPAD) for all population subgroups. The most highly exposed
p opulation subgroup, children 1

- 2 years old, had a risk estimate of 3.1% cPAD.

Residential/Aggregate Exposure and Risk : There are no existing or proposed residential uses of kasugamycin. Therefore, the only aggregate scenario assessed was chronic aggre gate risk, equivalent to chronic dietary risk, which is not of concern.

Occupational Exposure and Risk: Occupational handler exposures to kasugamycin were estimated assuming the maximum application rate, and label

- recommended equipment and methods, and standard assumptions with respect to the area treated. In the absence of chemical

specific data to assess handlers’ exposure and risk, HED relied on surrogate unit exposure data to estimate exposure and risk. HED assumed a single layer of clothing (base line) , without additional personal protective equipment (PPE). The resulting handler risk estimates, or MOEs, are all above 100 , and are thus below HED’s LOC. Depending on the scenario, MOEs ranged from 58,000 to 2,500,000.

Although a quantitative occ upational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational handlers. This assessment resulted in risk estimates that did not exceed HED’s LOC at baseline inhalation PPE. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of occupational post

- application inhalation exposure scenarios.

Review of H

uman R esearch : This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies (listed in Appendi x D) have been determined to require a review of their ethical conduct, have received that review, and have been determined to be ethically conducted.

2.0 HED Recommendations

HED recommend s in f

av or o f establish i n g tolerance s for the use of kasugamycin on fruiting vegetables (crop group 8

- 10) , pome fruits (crop group 11

- 10) , and walnuts, as described below.

2

. 1 Data Deficiencies

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### Page 5 of 8 2.2 Tolerance Considerations

2.2 .1 Enforcement Analytical Method

Adequate analytical methods are available for the purpose of tolerance enforcement. The lowest le vel of method validation (LLMV) was 0.040 ppm in each matrix tested.

2.2 .2 International Harmonization

There are no established or proposed Codex MRLs for kasugamycin in any food or feed crops. Tolerances were established in 40CFR §180.614 at 0.04 ppm to cover residues in/on imported tomatoes and peppers from Mexico . There are no issues regarding compatibility of the proposed tolerances because Mexico ado pts US tolerances, and/or Codex MRLs, for its export purposes. The proposed uses have been review ed by Canada’s PMRA ; EPA and PMRA have agreed to harmonize the recommended tolerances /MRLs , based on use of the OECD tolerance calculation procedure

.

2.2 .3 Recommended Tolerances

Note to RD: The tolerance expression should be revised to reflect specific coverage and compliance statements for the tolerances to be properly enforced in accordance with the Federal Food, Drug and Cosmetic Act ( FFDCA). Therefor e, the tolerance expression for kasugamycin cited in 40CFR §180.614[a] should be revised to state:

Tolerances are established for residues of kasugamycin, including its metabolites and degradates, in or on the commodities listed in the table below. Com pliance with the tolerance levels specified below is to be determined by measuring only kasugamycin (3

- O

- [2

- amino

- 4

- [(carboxyimino

- methyl)amino]

- 2,3,4,6

- tetradeoxy

- α

- D

- arabino

hexopyranosyl]

- D

- chiro

- inositol) in or on the commodity.

HED is now recommend ing the re moval of the established tolerance in imported fruiting vegetables at 0.04 ppm, concomitant with the establishment of a domestic crop group tolerance in fruiting vegetables, group 8

- 10, at 0.1 0 ppm.
HED has reviewed the available toxicological and residue chemistry studies for kasugamycin, and is recommending that permanent tolerances be established in/on the commodities in Table 2 .3.3 , at the specified levels

.Kasugamycin Human Health Risk Assessment DP Barcode D 4 15977



### Page 6 of 8 TABLE 2.3.3 Tolerance Summary for Kasugamycin. * Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Correct Commodity Definition Comments Vegetable, fruiting, Group 8 0.15 0.1 0 Vegetable, fruiting, group 8

- 10

Pome Fruit, Group 11 0.25 0.20 Fruit, pome, group 11

- 10 ( Provided that the label is amended to specify a 90

- day PHI for pome fruits. ) Walnut 0.04 0.0 4 * Tolerance levels as recommended within this document exclud e any consideration of antibiotic resistance impacts and / or concerns.



### 2.2 .4 Revisions to Petitioned

- f or Tolerances

Although a pome fruit crop group tolerance (fruit, pome, group 11

- 10) was requested, HED previously recommended for the establishment of individual tolerances in each commodity included in the crop group, since the residue data for apple, one of the repres entative commodities of crop g roup 11

- 10

, reflected a different use pattern than for pear, the other representative commodity . Specifically, the pre

- harvest interval (PHI) used in the apple field trials was significantly greater than the proposed label PH I ( 90 days instead of the proposed 30 )

, which was used in the pear field trials

. In order to harmonize HED’s recommended US tolerances with PMRA’s recently established MRLs in the various commodities, the rationales describ ed below were used

. Fruiting vegetables (group 8

- 10): When using the OECD tolerance calculation procedure for

non

- bell peppers, 3 of the 4 residue values entered into the OECD calculator were censored. Therefore , due to the small dataset, the calculator indicated that there was a high level of uncertainty associated with the recommended tolerance in non

- bell peppers

. Additionally , the maximum residue reported in non

- bell peppers w as 0.1 07 ppm (HAFT = 0.084 ppm)

, the calculated tolerance in tomatoes was 0.09 ppm, and the cal culated tolerance in bell peppers was 0.0 8 ppm . Therefore, HED has determined that a tolerance of 0.1 0 ppm is appropriate in the entire crop group.

Pome fruits (group 11

- 10): T he calculated tolerance in appl es , at a PHI of 90 days, was 0. 08
ppm

. T he calculated tolerance in pe a rs , at a PHI of 3 0 days (with a maximum residue of 0.172
ppm, HAFT = 0. 166 ppm) was 0. 3 0 ppm. Provided that the label is amended to specify a 90

- day PHI for pome fruits , HED has determined that a tolerance of 0.2 0 ppm is appropr iate in the entire
crop group.

Walnuts: The calculated tolerance in walnut s was 0.0 7 ppm. However, 2 of the 3 residue values entered into the OECD calculator were censored. Therefore, due to the small dataset, the calculator indicated that there was a high level of uncertainty associated with the recommended tolerance in walnuts. Given that 5 of 6 individual samples had residues less than 0.040 ppm, andKasugamycin Human Health Risk Assessment DP Barcode D 4 15977



### Page 7 of 8 that the sixth was reported at 0.0400 ppm, HED has determined that a tolerance of 0.0 4 ppm is
appr opriate in walnuts

.

2.3 Label Recommendations

2.3 .1 Recommendations from Residue Chemistry Reviews

The product label for Kasumin 2L (EPA File Symbol 66330

- UNU) should be amended as stipulated below and revised petition Sections B and F should be submitted.

General use directions : In its most recent risk assessment ( D376608; W.T. Drew; 13 July 2012)

, HED stated that t he label should s pecify that adjuvants may not be added to spray mixtures for crops other than pome fruits and walnuts , as adjuvants had not been used in the fruiting vegetables field trials

. Based on recent decisions by the Chemistry Sc ience Advisory Council (ChemSAC), that label revision is unnecessary; adjuvants may be used in spray mixtures applied
to fruiting vegetables

. Rotational crop statement : No rotational crop restrictions a re specified on the proposed label. T he label sho uld be revised to specify a 30

- day plant

- back interval ( PBI ) for all crops except those which are on the label as directly treated crops (which may be planted at any time)

.

PHI : For use on pome fruits , the product label should be amended to specify a minimum PHI of 90 days.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data and Percent Crop Treated Used in Dietary Assessment

An unrefined chronic aggregate dietary ( food and drinking water) exposure and risk assessment was conducted for kasugamycin ( D4 15989 ; W.T. Drew; 8 November 2013 ) using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

FCID), Version 3.16. This software uses 2003

- 2008 food consumption data from the US Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) . The residue inputs into the dietary model were the recomme nded tolerance level residues; default processing factors were used, with the exception of the apple juice processing factor, for which the 1.5X data

- derived factor was used. The dietary exposure assessment is based on the assumption of 100%CT for all cro ps with proposed uses on the kasugamycin label.

5.4. 2 Chronic Dietary Risk Assessment

Based on these highly conservative assumptions, chronic dietary risk estimates are less than or equal to 3.1 % of the cPAD for all population subgroups. Children 1

- 2 year s of age are the mostKasugamycin Human Health Risk Assessment DP Barcode D 4 15977



### Page 8 of 8 highly

- exposed subgroup, with a risk estimate of 3. 1 % of the cPAD, while the general US population had a risk estimate of <1 .0 % of the cPAD. Generally, HED is concerned when risk estimates exceed 100% of the PAD; therefore, all chronic dietary risk estimates are below HED’s level of concern (see Table 5. 4.3 )

.

5.4.3 Summary Table

TABLE 5.43 Summary of Chronic Dietary Exposure and Risk Estimates for Kasugamycin

. Population Subgroup* [Years of Age] cPAD (mg/kg/day) Dietary Exposure Estimate (mg/kg/day) % cPAD

General US Population 0.11 0.000526 <1.0 All Infants [< 1] 0.11 0.001899 1.7 Children [1

- 2] 0.11 0.003385 3.1 Children [3

- 5] 0.11 0.002015 1.8 Children [6

- 12] 0.11 0.000840 <1.0 Youth [13

- 19] 0.11 0.000367 <1.0 Adults [20

- 49] 0.11 0.000295 <1.0 Adults [50

- 99] 0.11 0.000264 <1.0 Females [13

- 49] 0.11 0.000299 <1.0
* Values for the population subgroup with the highest risk are in bold type

.