UN I TED STATES EN VIRONME NTA L PROTECTI ON AGENCY

WASHINGTON

, D.C. 20460



### MEMORANDUM

DAT E : June 18 ,20 14 OFFIC E OF CHEMICA L SA FETY

AND POLLU TIO N P REVEN TION



### SUBJEC T: Ma leic Hydrazide, and its Potassium 

### Salt: Qualitative Risk Assessmen t for Regis tratio n Review and Screen of the Hydrazine Impurity.



### PC Code : 051501,051503 

### DP Barcode : D413938



### Decision No. : 481781 

### Registration No

. : N/ A



### Petition No.: No t Applicable (N/A) 

### Regulatory Action : Registration Review


### Risk Assessment T ype: Qualitative 

### Case No

. : 0381



### TXR No.: N/A 

### CAS No.: 123-33-1, 51542

- 52-0



### MRID No.: N/A 40 

### CFR : 180.175

FROM : 

# hs an V Hwnmel, Risk Assessor and Chemist

# ~~**·** Ayaad Assaad, D

. V.M., Ph

. D., Toxico logist · 

### f) 

## ;17

_ Bonnie Cropp-Kohlligian, Dietary Exposure

### I:JJ?**-t?'~'l't\: ~**  James S Miller, Occupat i onal Ex posure**~i J.;~** **;-;** RAB IV, Hea lth Effec ts Division (7509P)



### THROUGH : Elissa Reaves, Ph.D., Branch Chief

RAB IV, Hea lth Effec ts Division (7509P



### TO : Ricardo Jones, RM # 51

Tom Moriarty, Team Leader
RMIB1, Pesticide Re-Evaluation Division (7508P)

Attached is t he Health Effect Division's (HED's) qualitative human health risk assessment for

maleic hydra zi de

, and its potassium salt, to support registration review.

H E D has prepared a human health risk assessment to support registration review for maleic hydrazide, and its potassium salt. Because oflow toxicity, and low frequency and severity of

incidents reported, the HED has determined that a qualitative risk assessment is appropriate for

maleic hydrazide, and its potas si um salt.

Page 1 of 19Introduction

Maleic hydrazide (1,2-dihydro-3,6-pyridazinedione) is a plant growth regulator and herbicide

that acts by inhibiting cell division in plants. Except where otherwise noted, the term "maleic hydrazide" in this document refers to the technical acid and the potassium salt of maleic

h ydrazide

. Maleic hydrazide is currently registered for food/feed use on potatoes

, on i ons
, and

tobacco. It is a l so registered for use on several terrestria l non-food crops. Maleic hydrazide is produced as an emulsifiable concentrate, water dispersible granule

, and in water soluble

pa ckaging. In the active registered end-use formulations, the active ingredient (ai) is in the form

of the potassium salt of maleic hydrazide and is present in the formulations from 21.7% to 80%.

Maleic h y drazide controls sucker (latera l shoots of tobacco plant) growth on tobacco

, inhibits

sprout growth in stored onions and potatoes, retards the growth of turf and controls sprouts on nonbearing apple and c i trus tree s, forest trees, and ornamental plants. It is a l so used as a herbicide to control quack grass
, wild onions, wild garlic and other undesirable weeds in

terrestrial nonfood crops
, residential lawns

, indu s trial areas and along roadsides and other rightsof-way. Maleic hydra zide presumed mode of action (MOA) is as a uracil anti-metabolite which

inhibits cell division in plants.

As part of the registration r eview process, HED has reassessed all the available toxicity studies

for maleic h ydrazide

, the need for toxicity data and reassessed the toxicity endpoints

, to ensure

con s istenc y with current Agency policies. The HE D Toxicology Science Advisory Council (ToxSAC) met on August 15, 2013 to review the toxicity database for maleic hydrazide andreeva l uated the poten t ial endpoints for risk assessment. A review o f incident data indicates 0 reported cases.

After reviewing the endpoi nts and th e previously selected points of departure, the ToxSAC

decided that the effects noted in the critical studies were not adverse and therefore not appropriate for us e as points of departure for risk assessment. Consequently

, the ToxSAC

concluded t here were no endpoints of concern and suggested that the maleic hydrazide risk

as sess m ent team utilize a qualitative

, and not quantitative

, approach to risk assessment.

Regulatory Conclusions and Recommendations

While exposure to maleic hydrazide i s po ssible via the diet

, as well as via residential and occupational use patterns

, HED has not identified any tox i cological endpoints for human health

risk assessment. Th erefore

, HED concludes that there is minimal risk and no quantitative dietary

, residential

, aggregate or occupat io nal risk assessments are needed and a qua lit at i ve risk

assessment is more appropriate.

There i s no concern for dietary exposure to maleic hydrazide

, so the existing tolerances for

residues of maleic h y dra z ide in 40 CFR 180.175 may be changed to exemptions from the requirement of a tol era nc e. Th e residue expression can be modified in the following manner:

An exemption from the requirement of a tolerance is es tablish ed for residues of the pesticide maleic hydrazide, inc ludi ng its metabolites and degradates, when used as a plant growth regulator or h erb icid e.

Page 2 of19

### Page 3 of 19

If the current tolerances for residues of maleic hydrazide are not changed to an exemption from the requirement of a tolerance, then tolerances will be needed for livestock commodities, and additional data will be required for livestock commodities.

Both t he Codex Alimentarius Commission and PMRA ha ve established maximum residue limits (MRLs) f or residues of maleic hydrazide, per se, on onion and potato at the same levels as are currently set in the U. S

. Changing the U. S. tolerance to an exemption from the requirement of

a tolerance will not cause any issues with Codex and PMRA MRLs. Neither Codex nor PMRA

have established tolerances on livestock commodities. The International Residue Status Sheet is included in Table 3 of Appendix I.

Maleic hydrazide contains an impurity, hydrazine, present in maleic hydrazide technical products

with a limit of 15 ppm. The impurity hydrazine is a carcinogen, with a Q 1 

### * of 3.0 (mg/kg/day)

- 1



### . The limit of 15 ppm for hydrazine in maleic hydrazide tec hnical products was set in 1982, at the conclusion of the Rebuttable Presumption Against Registration (RPAR), which returned maleic hydrazide to registration, provided maleic hydrazide technical products contained less than the 15 ppm limit for hydrazine ( EPA, 1982)

. Th e 15 ppm limit is still in effect. Therefore, for purposes of Registration Review, a highly conservative cancer dietary (food + water) assessment

, residential and occupational exposure screen was performed to re

- evaluate the safety of the 15 ppm hydrazine limit established at the conclusion of the RPAR. Based on a screen ing level

cancer risk assessment

, t he current upper limit of 15 ppm hydrazine is adequate to protect against

cancer r isk from the currently registered uses of maleic hydrazide

. For further details regarding

t he screening level carcinogenic risk assessment for hydrazine see Appendix II and the dietary exposure assessment (Cropp

- Kohlligian, B, 2014) and the occupational a nd residential exposure assessment (Miller, J. S., 2014).

The 15 ppm limit for contamination of hydrazine in maleic hydrazide technical products may be considered reassessed, and should remain in effect. However, any significant increases in currently reg istered uses or new uses of maleic hydrazide may need additional exposure

data to confirm this finding. Any future registration actions involving potential additional exposure to maleic hydrazide must consider exposure data needs in respect to hydrazine.

Note to PRD: Should the current tolerances for residues of maleic hydrazide not be changed to exemptions from the requirement of a tolerance, in addition to maintaining the existing potato and onion tolerances, additional tolerances for maleic hydrazide residues of

concern in livestock commodities will need to be established , requiring additional data for

livestock commodities

. Additionally, a new enforcement method will be needed for maleic hydrazide in livestock commodities.

Chemical Identity

The n omenclature of maleic hy drazide is presented in Table 1 of Appendix I . The physicochemical properties of maleic hyd razide are presented in Table 2 of Appendix I

. Maleic hydrazide is a solid at room temperature. It is very soluble in water and methanol. It has a very

### Page 4 of 19

low vapor pressure and the octanol/water partition coefficient indicates that it is unlikely to accumulate in biological tissues.

Hazard Identification and Dose Response Assessment

The toxicological database for maleic hydrazide is complete and sufficient to characterize potential hazards and to support Registration Review. Toxicological studies on maleic hydrazide and its potassium salt were evaluated for this assessment. Based on this analysis, HED has concluded that the parent and the potassium salt have the same toxicological effects. The toxicology database for maleic hydrazide is adequate/complete for registration review. T he available studies are listed below and in Appendix I, Tables I

- 4 and I

- 5

.

 Acute: Oral, dermal, inhalati on . Acute oral, inhalation, eye irritation, dermal irritation,

and skin sensitization

.

 Subchronic: 90

- day oral toxicity (rat, monkey). 21 day dermal (rat)

 Developmental toxicity: developmental toxicity (rat and rabbit)

 Reproduction: 1

- generation reproduction (rat)

 Chronic: combined oral chronic toxicity/carcinogenicity (rat). Chronic (dog). Carcinogenicity (mouse).

 Neurotoxicity: acute and subchronic (rat)

 Immunotoxic i ty: (rat)

 Metabolism: metabolism (rat)

 Other: mutagenicity battery.

Maleic hydrazide has a low acute toxicity (Category III or IV) by oral, dermal, and inhalation routes of exposure. It is mildly irritat ing to the skin (rabbit) and eyes (rat) and is not a dermal

sensitizer. Body weight loss was the only effect reported in long

- te rm studies in rats. A 10

- 14% loss was observed at doses of 500 and 1000 mg/kg/day, but only after 72 weeks of exposure. The chronic dog study showed no adverse effects up to the highest dose tested (1,000 mg/kg/day). A cancer study in mice with maleic hyd razide potassium salt showed negative carcinogenic potential at the highest dose tested. Additionally, two older special carcinogenicity studies, one in rats with perinatal exposure and one subcutaneous study in mice, showed no evidence of carcinogenicity. There were also no effects in the rat and rabbit developmental studies nor in the rat reproduction study at the limit dose

. Therefore there is no concern for susceptibility. Maleic hydrazide also demonstrated no neurotoxicity up to the limit dose in both the acute and subchronic neurotoxicity studies. In the inhalation study, decreased cumulative body weight gains (no bodyweight loss) were not considered adverse. There were also no effects on the respiratory tract. Therefore no adverse effects were observ ed in the inhalation study up to the highest concentration tested. In a 3

- week dermal toxicity study in rabbits, no dermal or systemic

effects were seen at the limit dose of 1,000 mg/kg/day. Maleic hydrazide did not show any evidence of immunotoxicity in the rat after 28

- day feeding study.

The Health Effects Division (HED) Toxicology Science Advisory Council (ToxSAC) met o n August 15, 2013 to review the database for m aleic hydrazide and to update endpoints according

### Page 5 of 19

to current policies. After reviewing the database and the previously selected points of departure, it was concluded that the effects noted in the critical studies (chronic toxicity/carcin ogenicity rat,

1

- year dog study, and 28

- day inhalation rat study) were not adverse. The data evaluation r ecords (DERs) for these critical studies were also updated to reflect the current study conclusions ( TXR

0056982 ). ToxSAC concurred that there was no concern for susceptibility since no effects were observed in either developmental rat or rabbit study nor in the rat reproduction study. The ToxSAC recommended not selecting endpoints and that the maleic hydrazide risk assessment team utilize a qualitative, and not quantitative, approach to risk assessment.

Dietary Exposure

Exposure to maleic hydrazide may occur from residues in the diet (food and water)

. However, a dietary exposure assessment is not needed for maleic hydrazide since no toxicity endpoints of

concern have been identified. Therefore, there is no dietary risk , and no further residue

chemis try data are needed to support currently registered uses.

Tolerance Assessment

Tolerances for maleic hydrazide on onion and potato commodities have been established in 40

CFR 180.175

. There is no concern for dietary exposure to maleic hydrazide, so these tolerances may be changed to an exemption from the requirement of a tolerance. The

residue expression should be updated to include metabolites and degradates.

Both t he Codex Alimentarius Commission and PMRA ha ve established maximum residue limits (MRLs) f or residues of maleic hydrazide, per se, on onion and potato at the same levels as are currently set in the U. S

. Changing the U. S. tolerance to an exemption from the requirement of

a tolerance will not cause any issues with Codex and PMRA MRLs. Neither Codex nor PMRA

have established tolerances on livestock commodities. The International Residue Status Sheet is

included in Table I

- 3 of Appendix I.

Residential Exposure

Exposure to maleic hydrazide from residential uses is possible. However, there is n o residential

risk since toxicity endpoints of concern were not identified in either the dermal or inhalation

studies

.

Occupational Exposure

Occupational exposure to maleic hydrazide from agricultural and residential uses is possible.
However, an occupational exposure assessment is not needed since no toxicity endpoints of concern have been identified. No occupational exposure data are needed.

Volatilization

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for maleic hydrazide at this time primarily because no adverse

effects were observed in the inhalation study up to the highest concent ration tested

, and maleic

### Page 6 of 19

hydrazide has a vapor pressure ( 7.5 x10

- 8 

### mm Hg at 25  C ) ). Although a quantitative post

application inhalation exposure assessment for maleic hydrazide was not performed, a screening

level cancer inhalation exposure assessment fo r the impurity hydrazine was performed for

handlers. This cancer exposure scena rio is representative of a worst case inhalation exposure for both maleic hydrazide and its impurity hydrazine, and should be considered protective of current
post

- application inhalation exposure scenarios related to maleic hydrazide

.

Endocrine Disruptor Screening Program

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicit y, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturatio n, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As par t of its preliminary risk assessment for registration review of maleic hydrazide , EPA reviewed the available data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by

FF DCA section 408(p), maleic hydrazide is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required

determinat ions. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and

establish a dose

- response relationship between the dose and the E, A, or T effect. Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, E PA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 ( http://www.regulations .gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 ) and includes some pesticides scheduled for registration review and chemicals found in water

. Neither of these lists should be construed as a list of known or likely endocrine disruptors. For further

infor mation on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website ( http://www.epa.gov/endo/ ).

### Page 7 of 19

Spray Drift ( For all a gricultural /commercial outdoor)

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential so urce of exposure from the ground application method employed for maleic hydrazide

. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spr ay drift management practices (see the Agency’s Spray Drift website for more information 1 

### . The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce

off

- target drift with specific products with significant risk estimates associated with drift.

Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

to maleic hydrazi de and any other substances and maleic hydrazi de does not app ear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that maleic hydrazide has a common mechanism of toxicity with other substances. For information regarding EPA’s effort s to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

References

Abdel

- Saheb, Ibrahim, 2005. “Tier 1 Drinking Water Assessment for Maleic Hydrazide Use on

Fallow Land.” D313422. EPA memorandum dated February 17, 2005.

Biancifiori, C. 1970. Hepatomas in CBA/Cb/Se mice and liver lesions in golden hamsters
induced by hydrazine sulfate. J. Natl. Cancer Inst. 44: 943.

Cropp

- Kohlligian, B. 2014. “Hydrazine Dietary Exposure Assessment.” D420404

. EPA

memorandum dated June 4 , 2014.

Daiss, Rebecca , 2009. “ Maleic Hydrazide: Human Health Risk Scoping Document in Support of Registration Review ,” D362552 . EPA memorandum dated May 14, 2009

.

1 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm

### Page 8 of 19

EPA, 1982. “Rebuttable Presumption Ag ainst Registration: Decision Document on Maleic Hydrazide.” Office of Pesticide Programs document, June, 1982.

Hummel, Susan, 2014. “ Maleic hydrazide and salts Registration Review . Summary of Analytical Chemistry and Residue Data. And Maleic Hydrazide and Salts Reregistration Data. Storage Stability Data on Potatoes, Ruminant and Poultry Metabolism, Analytical Methods and Feeding

Studie s.” EPA memorandum dated May 14 , 2014.

IRIS, 2002, “ Integrated Risk Information System : Hydrazine/Hydrazine sulfate (CASRN 302

- 01

- 2) ,” U.S. Environmental Protection Agency, National Center for Environmental Assessment,
Office of Research and Development, Washington, DC.

, web page
http:// www.epa.gov/IRIS/subst/0352.htm , last updated 12/03/2002

.

Miller, J. S. 2014. “ Hydrazine

. Occupational and Residential Exposure Cancer Screen for
existing uses of Maleic Hydrazide/Hydrazine on Turf, Tobacco, Potatoes, Ornamental shrubs and

trees, and for control of Onions and Garlic in dormant turf.” D420405 . EPA memorandum

dated June 4, 2014.

RED, 1994. “Reregistration Eligibility Decision (RED): Maleic Hydrazide” Environmental Protection Agency Document, EPA 738

- R

- 94

- 010, June 1994.

TRED, 2005. “ To lerance Reassessment Eligibility Decision on Maleic Hydrazide .” 

### EPA

memorandum dated September 22, 2005 from Susan Lewis to Debra Edwards.

### Page 9 of 19

Appendix I

Tables for Chemical Identity and Tolerances

Chemical Identity

The nomenclature of maleic hydrazide is presented in Table A.1. The physicochemical properties of maleic hydrazide are presented in Table A.2. Maleic hydrazide is a solid at room temperature. It is very soluble in water and methanol. It has a very low vapor pressure and the

octanol/water partition coefficient indicates that it is unlikely to accumulate in biological tissues.

Hydrazine has a high vapor pressure ( 14.4 mm Hg at 25 °C ) and a low octanol water partition

coefficient of 0.08 , indicating that it is not likely to accumulate in biological tissues.

TABLE I

- 1. Test Compound Nomenclature

Chemical structure

Common name Maleic hydrazide

Company experimental name MH

IUPAC name 6

- hydroxy

- 2H

- pyridazin

- 3

- one

CAS name 1,2

- dihydro

- 3,6

- pyridazinedione

CAS registry number 123

- 33

- 1

Molecular Formula C4

- H4

- N2

- O2

Formula Weight 112. 1

End

- use product (EP) Not applicable

Chemical structure

Common name Maleic hydrazide , potassium salt

Company experimental name N/A

IUPAC name pyridazindi one , 6

- hydroxy, monopotassium salt

CAS name 1,2

- dihydro

- 3,6

- pyridazinedione

, monopotassium salt

CAS registry number 28382

- 15

- 2

Molecular Formula C4

- H4

- N2

- O2.K

### Page 10 of 19

TABLE I

- 1. Test Compound Nomenclature

Formula Weight 151.2

End

- use product (EP) Not applicable

Structure

Common name Maleic hydrazide glucoside

Company experimental name MHG

Chemical name 3

- β

- D

- glycopyranosyl

- oxy

- 6

- pyridazinone

Chemical structure

Common name Pyridazinone

Company experimental name M

- 10

IUPAC name 3(2H)

- Pyridazinone

CAS name 3(2H)

- Pyridazinone

CAS registry number 504

- 30

- 3

Molecular Formula C4

- H4

- N2

- O

Formula Weight 96.1

End

- use product (EP) Not applicable

Hydrazine Structure

Chemical Structure H 2 N

— NH 2

Common name Hydrazine

Company experimental name NA

IUPAC name Hydrazine

CAS name Hydrazine

CAS registry number 302

- 01

- 2

Molecular Formula H 2 N

— NH 2 Formula Weight 32.0

TABLE I

- 2. a. Physicochemical Properties of Technical Grade Test Compound

– Maleic Hydrazide

.
Parameter Value Reference 1

Melting point/range 292  C Product Chemistry RED Chapter (D193500, W. Smith, 08/20/93)

pH Not available

Density Not available

Water solubility 4507 ppm at 25  C USDA/ARS Pesticide Properties Database

Solvent solubility 4179 ppm in methanol at 25  C

### Page 11 of 19

TABLE I

- 2. a. Physicochemical Properties of Technical Grade Test Compound

– Maleic Hydrazide

.
Parameter Value Reference 1

Vapor pressure 7.5 E

- 8 at 25  C

Dissociation constant, pK a 5.62 at 20  C

Octanol/water partition

coefficient 0.011 at pH 7

UV/visible absorption Maxima at Molar Absorption

λ max Coefficient

Acidic conditions:

206 nm 1.259 nm 14,300

306 n m 0.894 nm

2,540

Neutral conditions:

208 nm 1.179 nm 13,400

3 10 nm 0.886 nm 2,520

Basic conditions:

222 nm 1.296 nm 14,700

338 nm 0.827 nm 2,350 MRID 4 7270501

D 346501 , TMorton 8/14/08

TABLE I

- 2. b. Physicochemical Properties of Maleic Hydrazide Impurity, Hydrazine

.
Parameter Value Reference 1

Water solubility miscible EPA Air Toxics Web Site http://www.epa.gov/ttn/atw/hlthef/hydrazin.html Solvent solubility NA

Vapor pressure 14.4 mm Hg at 25 °C

Octanol/water partition

coefficient (log K ow ) 0.08

### Page 12 of 19



### Table I

- 3 . Maleic Hydrazide (PC Code 0515 01; Date of Request 02/21/14 )

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 1 Codex 2

40 CFR 180.175

Plants & Livestock: Maleic Hydrazide (1,2

- dihydro

- 3,6

- pyridazinedione) 1,2

- dihydro

- 3,6

- pyridazinedione Maleic hydrazide

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 Codex 2

Onions ( 15 ) 15 15 onion, bulb, garlic,

shallot

Potato ( 50 ) 50 50

Milk ( 0.01 ) Meat of cattle, goats, horses, and sheep ( 0.02 )

Liver of cattle, goats, horses, and sheep ( 0.02 )

Kidney of cattle, goats, horses, and sheep ( 0.1 )

Fat of cattle, goats, horses, and sheep ( 0.02 )

MRLs With NO US Equivalent

Carrot roots 30

Garden beet roots 30 Rutabaga roots 30

Completed: M. Negussie; 02/28/14

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

2) A food additive known as maleic hydrazide (1,2

- dihydro

- 3,6

- pyridazinedione) may be present in potato, chips when used in accordance with the following conditions:

(i) The food additive is present as a result of the application of a pesticide formulation co ntaining maleic hydrazide to the growing potato plant in accordance with directions registered by the U.S. Environmental Protection Agency.

(ii) The label of the pesticide formulation containing the food additive conforms to labeling registered by the U.S. Environmental Protection Agency.

(iii) The food additive is present in an amount not to exceed 160 parts per million by weight of the finished food.

### Page 13 of 19

Table. I

- 4. Acute Toxicity Profile

- Maleic Hydrazide

Guideline

No. Study Type MRID(s) R esults Toxicity Category 870.1100 Acute oral [Rat] 00079657 LD 50 > 5000

m g/kg IV

870.1200 Acute der m al [Rabbit] 00079658 LD 50 > 2000

m g/kg IV

870.1300 Acute inhalation [Rat] 41185401 L C 50 > 4.0

m g/L IV

870.2400 Acute eye irritation [Rabbit] 00079661 slight irritation III

870.2500 Acute der m al irritation

[Rabbit] 00079660 slight irritation IV

870.2600 Skin sensitization [Guinea

pig] 41289101 negative N/A

Table I

- 5. Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type MRID No.(year)/

Classification /Doses Results

870.3200

21/28

- Day der m al toxicity (rat) 4 1289102 (1989) (Acceptable/Guideline) 0, 100, 500, 1000 mg/kg/day NOAEL = 1000 m g/kg/day (der m al toxicity and

syste m ic toxicity)

LOAEL = not established.

870.3465

21/28

- Day inhalation toxicity (rat) 47636401 (2008) Acceptable/Guideline 0, 0.05, 0.1, 0.5, 1.0 mg/L NOAEL = 1.0 mg/L/day.

LOAEL = not established

870

- 7800 Immunotoxicity, incorporated with Subchronic Neurotoxicity

- Rats

under MRID #

48881902. 48881902 (Subsets (B & C) (2010) (Acceptable/Guideline) 0, 1000, 10,000, or 20,000 ppm (Equivalent to 0, 85, 841, 1688 mg/kg bw/day (males), and 0, 86, 873, and 1733 mg/kg bw/day (females). Systemic and immuno

- toxic: NOAEL = 20,000 ppm (1688 mg/kg bw/da y)

LOAL was not observed.

870.3700a

Prenatal develop m

ental (rat) 41458201, 41702901(1990)

( Acceptable/ Guideline) 0, 30, 300, 1000 m

g/kg/day Maternal NOAEL = 1000 m g/kg/day

LOAEL = not established. Developmental NOAEL = 1000 m g/kg/day

LOAEL = not established.

870.3700a

Prenatal develop m

ental (rat) 40874202, 41055903 (1988,

1989) ( Acceptable/Guideline)
0, 400, 800, 1200,

1600 m g/kg/day Maternal NOAEL = 1600 m g/kg/day

LOAEL = not established. Developmental NOAEL = 1200 m g/kg/day

LOAEL = 1600 m g/kg/day based on slightly

increased incidence of nu m ber of fetuses with

m inor skeletal variations.

870.3700b Prenatal developmental (rabbit) 00128721, 40985311 (1983, 1988) Acceptable/Minimum 0, 100, 300, 1000 mg/kg/day Materna l NOAEL = 1000 mg/kg/day

LOAEL = not established. Developmenta l NOAEL = 1000 mg/kg/day

LOAEL = not established.

### Page 14 of 19

Table I

- 5. Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type MRID No.(year)/

Classification /Doses Results

870.3800 Reproduction (rat) 00128720 (1983) ( Acceptable/ guideline) Parental/Reproductive / Offspring NOAEL = 791

m g/kg/day

. Parental/Reproductive / Offspring L OAEL = 2405

m g/kg/day based on reduce weight gain for both adults

and pups

870.4300

Chronic toxicity/ carcinogenicity (rat) 42570101, 42770401 (1991, 1993) (Acceptable/Guideline) 0, 25, 500, 1000 mg/kg/day for

104 weeks NOAEL = 1,000 m g/kg/day

LOAEL = not established.

870.4100b

Chronic toxicity (dog) 42214101, 42248101 (1991) (Acceptable/Guideline) 0, 750, 2500, 25000 ppm (M: 0, 29, 87, 974; F: 29, 105, 974 mg/kg/day) for 52 weeks NOAEL = 974 m g/kg/day (HDT)

LOAEL = not established.

870.4200 Carcinogenicity ( m ouse) 00097886, 00098466 (1981) (Acceptable/Guideline) 0, 1000, 3200, 10,000 ppm for 23 months mg/kg/day NOAEL = 10,000 ppm (M: 1545 m g/kg/day; F:

1811 m g/kg/day)

LOAEL = not established.

N o evidence of carcinogenicity

Cytogenetics

870.5375

Chro m oso m e aberrations in vitro 41147302 (1989) ( Acceptable/Guideline) Negative in the absence of S

- 9 at doses up to 4640 μg/ m l in Chinese ha m ster ovary (CHO) cells. In the

presence of S

- 9, a statistically significant (p<0.01)

increase in aberration bearing cells was found at 10,000 μg/ m l cultures at the 12

- hour sa m pling, but not the 24

- hour sa m pling. There was a m arked increase in os m otic

pressure at 10,000 μg/ m

l. The apparent positive results

in this assay are considered to be equivocal because of

the possible confounding effect of increased os m otic

pressure

.

Cytogenetics ( in vivo )

870.5385 41660001 (1990) ( Acceptable/Guideline) Male and fe m ale B6C3F1 m ice were given a single intraperitoneal injection of the potassium salt of m aleic hydrazide at dose levels up to 1100 m g/kg, the level causing death. There were no s i gnificant increases in

sister chro m atid exchanges over control levels were found in any treated m ale or fe m ale dose group.



### Table I

- 5. (cont). Subchronic, Chronic and Other Toxicity Profile

### Page 15 of 19

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

Other Effects

- DNA damage/repair

in B. subtilis (rec

- assay)

870.5900 41176601, 41176602 (1988)

( Acceptable /Guideline) Cultures of strain M45 ( re c

- ) and strain H17 ( rec +) of

Bacillus subtilis were treated with the potassium salt

of m aleic hydrazide or technical grade m aleic hydrazide at doses up to 10,000 μg/plate, both in the

presence or absence of S

- 9 and survival index was counted. It was concluded that both the potassium

salt of m aleic hydrazide or m aleic hydrazide appear

to be reco m

binogenic, i.e., have the potential to affect

DNA repair processes at the at the extremely high dose levels of 5000 to 10,000 μg/plate both with and

without S

- 9.

Other Effects

870.5550

- sister chro m atid exchange assay in vitro 41147303 (1989) ( Acceptable/Guideline) The potassium salt of m aleic hydrazide was tested in a sister

- chro m atid exchange assay using Chinese

ha m ster ovary (CHO) cells in vitro at doses up to 10,000 μg/ m

l. Significant increases in sister

chro m atid exchanges were observed in cultures both

without and with S

- 9 at cytotoxic doses of 10,000 μg/ m l without S

- 9 and 3200 and 10,000 μg/ m L with

S

- 9.

870.6200a

A cute Neurotoxicity

- Rats 48881901 (2012) ( Acceptable/guideline ) 0 or 2000 mg/kg LOAEL could not be determined. NOAEL = 2000 mg/kg no adverse, treatment

- related effects were observed in clinical signs, absolute body weight, food consumption,

FOB observation s, motor activity, gross or neuro

histopathological examination or brain weight.

870.6200b Subchronic Neurotoxicity

- Rats 48881902 (Subset A) (2010) (Acceptable/guideline) 0, 1000, 10,000, or 20,000 ppm (equivalent to 0, 59, 623, and 1241 mg/kg bw/day (males), and 0, 72, 734, and 1463 mg/kg bw/day (females). NOAEL = 10,000 ppm (623 mg/kg bw/day) LOAEL = 20,000 ppm (equivalent to 1241 mg/kg bw/day) based on reduced body weight gain, increased food consumption, and reduced food efficiency in males.

No adv erse, treatment

- related effects on mortality, clinical signs, neurobehavioral testing results (FOB and motor activity), gross necropsy findings, brain weight,

or neuro

- histopathological results.

Table I

- 5 (cont). Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Result

s

### Page 16 of 19

870.7485

Metabolism and phar m acokinetics (Rat) 41571701, 41679701,

42432301 (1990) ( Acceptable/Guideline ) Following oral or intravenous dosing of rats, m aleic hydrazide is excreted m ainly in the urine (76

- 87% at 7 days) with lesser a m ounts in the feces (5

- 15%). Less

than 1% was found in expired air. There was no evidence

of bioaccu m

ulation of radioactivity in any tissue or organ. There were no differences between the sexes. Four

- hour

urine contained m ostly unchanged m aleic hydrazide (>60% of urinary radioactivity in m ales and >80% in

fe m ales) with a lesser a m ount of the sulfate conjugate of

m aleic hydrazide. No other significant m etabolites were present in the urine. Fecal m etabolites were not identified.

### Page 17 of 19

Appendix II : C onservative Human Health Screening Level Cancer Assessment for Hydrazine Impurity in Maleic Hydrazide Technical Grade Products

.

Maleic hydrazide t echnical grade products contain hydrazine as a contaminant and hydrazine has been associated with tumor induction. In 1982, at the close of the maleic hydrazide s pecial

r eview (th e n called Rebuttable Presumption Against Registration or RPAR), the Agency established an upper limit for hy drazine at 15 ppm in technical grade products containing maleic hydrazide. The Agency determined that , at this upper limit, there was no concern for hydrazine

b ased on estimates of excess lifetime carcinogenic risks to humans considering both dietary and worker exposure. This upper limit remains in effect and was re

- evaluated as part of the maleic hydrazide registration review

.

The screening level aggregate cancer risk was estimated to be 1 x 10

- 6 

### for the U. S. General Population. For occupational exposures, the estimated screening level cancer risk was 4.0 x 10

-

7 

### for private handlers, and 2.0 x 10

- 5 

### for commercial handlers. Estimated cancer risks from post

application activities was estimated to be of lower risk

.

H ighly conservative human health screening level cancer risk assessments for hydrazine as a contaminant in maleic hydrazide technical grade products at the Agency stipulated limit of 15 ppm were completed for dietary (food + water) , residential and occupational exposures. An aggregate risk assessment was also completed for dietary (food and water) and residential

exposures. No hydrazine chemical

- specific data were available for risk assessment with the exception of fate data obtained from open literature. Hence, screening l evel dietary assessments for hydrazine relied on available residue chemistry data for maleic hydrazide and/or were based on maximum use rates for maleic hydrazide and the assumption that the ratio of parent to hydrazine in the maleic hydrazide technical gr ade products remains unchanged in formulated

end

- use products and in/on plants through application/deposition/translocation and beyond. Screening level occupational and residential exposure assessments assumes the maximum application rate, a high end numb er of days exposed per year, and exposure every year for a number of years for the scenario which produces the largest exposure, along with the assumption of the same ratio of maleic hydrazide to hydrazine.

Maleic hydrazide and its potassium salt are cu rrently registered for food/feed uses on onions and potatoes, as well as several terrestrial non

- food crops, including turf, fallow land and golf courses. Its major use is on tobacco. Maleic hydrazide is formulated as an emulsifiable concentrate, water d ispersible granule, and in water soluble packaging. Application equipment used includes ground boom, backpack, mechanically pressurized handgun sprayers, and fixed wing aircraft. There are several currently registered technical grade products (400

- 97, 19 713

- 25,

19713

- 26 and 51873

- 10) with maleic hydrazide at 95% or higher. Given the 15 ppm ( 0.0015% ) Agency stipulated limit for hydrazine in maleic hydrazide technical grade products , this would mean an estimated ratio of parent:hydrazine in the maleic hydrazide techni cal grade product s of roughly 100%:0.0015% or 1:1.5E

- 5. Hence, application rates for hydrazide were estimated from the maximum application rates for maleic hydrazide multiplied by 0.0015%.

Hazard Identification and Dose Response Assessment

### Page 18 of 19

The US EPA National Center for Environmental Assessment (NCEA) has classified hydrazine as a Group B2, probable human carcinogen (USEPA, 1999). The classification is based on tumors identified in mice, rats, and hamsters following oral, inhalat ion or intraperitoneal administration of hydrazine and hydrazine sulfate. Hydrazine was mutagenic in numerous assays. Increased incidences of lung and liver tumors were observed in mice by inhalation, in their drinking water, via gavage and injection. T umors in the nasal cavity also were observed in rats and hamsters exposed by inhalation ( Biancifiori, C. 1970. ).

For the HED cancer dietary screen , the residential exposure screen, and the occupational

exposure screen , the oral cancer slope factor is most relevant. NCEA relied on a hydrazine sulfate (in water) gavage study in mice for the dose

- response data for the oral cancer slope

factor. Liver hepatomas were observed in CBA/cb/Se male mice (Biancifiori, 1970). The oral cancer slope factor f

or hydrazin e is 3.0 (mg/kg/day)

- 1 

### using the l inearized multistage procedure

. The carcinogenicity of hydrazine is discussed in EPA’s Integrated Risk Information System (IRIS, 2002). For a detailed discussion of confidence in the potency estimates, please see the

IRI S website.

Dietary Exposure/Risk Assessment

Reference: D 420404 , B. Cropp

- Kohlligian, 6/ 12 /14



### Screening level cancer aggregate dietary ( food and drinking water ) exposure and risk

assessment s were conducted 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 U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, What We Eat in America, (NHA NES/WWEIA).

Anticipated residues in food commodities were estimated as follows. Average residues of hydrazine in/on dry bulb onions and potatoes were estimated at 0.0015% of the average residues of parent determined in field trials conducted with paren t at the maximum registered use rates of maleic hydrazide. Since maleic hydrazide

- treated potato culls and potato processing waste can be fed to cattle, residues of hydrazine in cattle tissues and milk were estimated at 0.0015% of the

maximum total residu es of maleic hydrazide in cattle tissues and milk (i.e., total radioactive residue (TRR) levels from the goat metabolism study) from feeding a reasonably balance ruminant diet. In the absence of specific processing data for hydrazine, DEEM default

process ing factors were used for potato flakes/granules/flour (6.5) and dried beef (1.92) and the maximum theoretical concentration factor for potato (5.0) was used for potato chips. In the absence of percent crop treated data for maleic hydrazide, 100% crop tre ated was assumed. The anticipated residue estimates used in this assessment were approved by the Anticipated Residue Focus Group of ChemSAC (4/15/14). Tier 1 EDWC (1.E

- 6 ppm) for hydrazine was also used.

The e stimated exposure of the general U.S. population to hydrazine (food and drinking water) from the registered uses of maleic hydrazide and assuming that the technical grade of the maleic hydrazide contains 15 ppm (0.0015%) of hydrazine is 2.6 E

- 07 mg/kg/day. Applying the Q 1 

### * of 3.0 (mg/kg/day)

- 1 

### to the exposure

, results in a screening level cancer risk estimate of 8 x 10

- 7



### . This estimate is consider ed conservative and does not underestimate risk. The major contributors were potatoes and potato chips.

### Residential and Occupational Exposure/Risk

Reference: D 420405

, S . Miller, 6/ 12 /14



### Screening level c ancer risk estimates were calculated using a linear low

- dose extrapolation approach in which a Lifetime Average Daily Dose (LADD) is first calculated and t hen compared with a Q 1 

### * that has been calculated for Hydrazine based on dose response data in the appropriate toxicology study (Q 1 

### * = 3.00 (mg/kg/day)

- 1 

### ). Absorbed average daily dose (ADD) levels were used as the basis for calculating the LADD. Dermal and inhalation ADDs were first added together to obtain combined ADD s. LADD s were then calculated and compared to the Q 1 

### * to obtain cancer risk estimates. The LADD assumed a maximum application rate, hydrazine impurity present at the limit of 15 ppm, and the minimum level of Personal Protection Equipment (PPE) includi ng long

- sleeved shirt, long pants, chemical resistant gloves, shoes and

socks. The screening level cancer risk estimate for the most conservative residential handler

scen arios (pressurized hand wand on turf) was 5 x 10

- 7



### . The screening level cancer risk estimate for the most conservative residential post

- application scenarios (adult golfer) was 1 x 10

- 8



### . These risk estimates can be combined and result in a screening le vel cancer risk estimate of 5 x 10

- 7



### .

Screening level occupational c ancer risk estimates were provided for hydrazine. The fallow land exposure scenario was the most conservative. The maximum application rate was assumed, along with the maximum acreage treated per day, the minimum PPE (baseline) , the maximum days per year exposed ( 10 days per year for private growers and 30 days per yea r for commercial applicators ), and the label required restricted entry interval (REI) is 12 hours. It is assumed that

h andlers would be exposed for 35 years out of a lifespan. The screening level cancer risk estimate for the most conservative occupational handler scenarios (aerial on fallow land) was 2 x 10

- 5 

### for private growers (growers applying pesticide to their own lan d) and 7 x 10

- 5 

### for commercial applicators. The screening level c ancer risk estimate for the most conservative occupational post

- application scenarios ( tobacco handset irrigation ) was 5.1 x 10

- 7 

### , based on the default assumption of 25% of the application is available for transfer on day 0 following the application and the residues dissipate at a rate of 10% each following day.

Aggregate Exposure Risk Assessment

Aggregate Cancer Risk Assessment is conducted by adding the exposures from dietary exposure and residential exposure. The screening level aggregate cancer risk was estimated for the U. S. General Population to be 1 x 10

- 6 

### . For occupational exposures, t he estimated screening level

cancer risk was 2 x 10

- 5 

### for private handlers, and 7 x 10

- 5 

### for commercial handlers. Estimated cancer risks from post

- application activities w ere estimated to be of lower risk

.