UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DATE: June 18,2014 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: Maleic Hydrazide, and its Potassium Salt: Qualitative Risk Assessment for 

Registration Review and Screen of the Hydrazine Impurity. 

PC Code: 051501,051503 DP Barcode: D413938 

Decision No.: 481781 Registration No.: N/ A 

Petition No.: Not Applicable (N/A) Regulatory Action: Registration Review 

Risk Assessment Type: 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: hsan V Hwnmel, Risk Assessor and Chemist ~~· Ayaad Assaad, D.V.M., Ph.D., Toxicologist · f) ;17 _ Bonnie Cropp-Kohlligian, Dietary Exposure I:JJ? -t?'~'l't\:~ 

James S Miller, Occupational Exposure ~iJ.;~ ;-; 

RAB IV, Health Effects Division (7509P) 

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

RAB IV, Health Effects Division (7509P 

TO: Ricardo Jones, RM#51 

Tom Moriarty, Team Leader 

RMIB1, Pesticide Re-Evaluation Division (7508P) 

Attached is the Health Effect Division's (HED's) qualitative human health risk assessment for 

maleic hydrazide, and its potassium salt, to support registration review. 

HED 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 potassium salt. 

Page 1 of 19 
Introduction 

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 

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

tobacco. It is also registered for use on several terrestrial non-food crops. Maleic hydrazide is 

produced as an emulsifiable concentrate, water dispersible granule, and in water soluble 

packaging. 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 hydrazide controls sucker (lateral 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 citrus trees, forest trees, and ornamental plants. It is also used as a 

herbicide to control quack grass, wild onions, wild garlic and other undesirable weeds in 

terrestrial nonfood crops, residential lawns, industrial areas and along roadsides and other rightsof-way. Maleic hydrazide presumed mode of action (MOA) is as a uracil anti-metabolite which 

inhibits cell division in plants. 

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

for maleic hydrazide, the need for toxicity data and reassessed the toxicity endpoints, to ensure 

consistency with current Agency policies. The HED Toxicology Science Advisory Council 

(ToxSAC) met on August 15, 2013 to review the toxicity database for maleic hydrazide andreevaluated the potential endpoints for risk assessment. A review of incident data indicates 0 

reported cases. 

After reviewing the endpoints and the previously selected points of departure, the ToxSAC 

decided that the effects noted in the critical studies were not adverse and therefore not 

appropriate for use as points of departure for risk assessment. Consequently, the ToxSAC 

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

assessment team utilize a qualitative, and not quantitative, approach to risk assessment. 

Regulatory Conclusions and Recommendations 

While exposure to maleic hydrazide is possible via the diet, as well as via residential and 

occupational use patterns, HED has not identified any toxicological endpoints for human health 

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

residential, aggregate or occupational risk assessments are needed and a qualitative risk 

assessment is more appropriate. 

There is no concern for dietary exposure to maleic hydrazide, so the existing tolerances for 

residues of maleic hydrazide in 40 CFR 180.175 may be changed to exemptions from the 

requirement of a tolerance. The residue expression can be modified in the following manner: 

An exemption from the requirement of a tolerance is established for residues of the 

pesticide maleic hydrazide, including its metabolites and degradates, when used as a plant 

growth regulator or herbicide. 

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 the Codex Alimentarius Commission and PMRA have established maximum residue limits 

(MRLs) for 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 Q1* of 3.0 (mg/kg/day)-1. 

The limit of 15 ppm for hydrazine in maleic hydrazide technical 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). The 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 screening level 

cancer risk assessment, the current upper limit of 15 ppm hydrazine is adequate to protect against 

cancer risk from the currently registered uses of maleic hydrazide. For further details regarding 

the screening level carcinogenic risk assessment for hydrazine see Appendix II and the dietary 

exposure assessment (Cropp-Kohlligian, B, 2014) and the occupational and 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 registered 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 nomenclature of maleic hydrazide is presented in Table 1 of Appendix I. The 

physicochemical properties of maleic hydrazide 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. The 

available studies are listed below and in Appendix I, Tables I-4 and I-5.

 Acute: Oral, dermal, inhalation. 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)

 Immunotoxicity: (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 irritating to the skin (rabbit) and eyes (rat) and is not a dermal 

sensitizer. Body weight loss was the only effect reported in long-term 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 hydrazide 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 observed 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 on 

August 15, 2013 to review the database for maleic 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/carcinogenicity rat, 

1-year dog study, and 28-day inhalation rat study) were not adverse. The data evaluation records 

(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 

chemistry 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 the Codex Alimentarius Commission and PMRA have established maximum residue limits 

(MRLs) for 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 no 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 concentration tested, and maleic 
Page 6 of 19

hydrazide has a vapor pressure (7.5 x10-8 mm Hg at 25C)). Although a quantitative postapplication inhalation exposure assessment for maleic hydrazide was not performed, a screeninglevel cancer inhalation exposure assessment for the impurity hydrazine was performed for 

handlers. This cancer exposure scenario 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, neurotoxicity, 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 maturation, 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 part 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 

FFDCA 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 

determinations. 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, EPA 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 

information 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 agricultural /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 source 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 spray drift 

management practices (see the Agency’s Spray Drift website for more information1. 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 hydrazide and any other substances and maleic hydrazide does not appear 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 efforts 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 Against 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 

Studies.” 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. “Tolerance 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

NH

N

OH

O

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 pyridazindione, 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 H2N—NH2

Common name Hydrazine

Company experimental name NA

IUPAC name Hydrazine

CAS name Hydrazine

CAS registry number 302-01-2

Molecular Formula H2N—NH2

Formula Weight 32.0

TABLE I-2.a. Physicochemical Properties of Technical Grade Test Compound – Maleic Hydrazide.

Parameter Value Reference1

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 Reference1

Vapor pressure 7.5 E-8 at 25 C

Dissociation constant, pKa 5.62 at 20 C

Octanol/water partition 

coefficient

0.011 at pH 7

UV/visible absorption Maxima at Molar Absorption 

 λmax Coefficient

Acidic conditions: 

 206 nm 1.259 nm 14,300

 306 nm 0.894 nm

2,540

Neutral conditions: 

 208 nm 1.179 nm 13,400

 310 nm 0.886 nm 2,520

Basic conditions: 

 222 nm 1.296 nm 14,700

 338 nm 0.827 nm 2,350

MRID 47270501

D346501, TMorton 8/14/08

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

Parameter Value Reference1

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 Kow)

0.08
Page 12 of 19

Table I-3. Maleic Hydrazide (PC Code 051501; Date of Request 02/21/14)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex2

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 Mexico1 Codex2

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 containing 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) Results Toxicity

870.1100 Acute oral [Rat] 00079657 LD Category 50 > 5000

mg/kg

IV

870.1200 Acute dermal [Rabbit] 00079658 LD50 > 2000

mg/kg

IV

870.1300 Acute inhalation [Rat] 41185401 LC50 > 4.0

mg/L

IV

870.2400 Acute eye irritation [Rabbit] 00079661 slight irritation III

870.2500 Acute dermal 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 dermal toxicity (rat)

41289102 (1989) 

(Acceptable/Guideline)

0, 100, 500, 1000 mg/kg/day

NOAEL = 1000 mg/kg/day (dermal toxicity and

systemic 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/day)

LOAL was not observed.

870.3700a

Prenatal developmental (rat)

41458201, 41702901(1990)

(Acceptable/Guideline)

0, 30, 300, 1000 mg/kg/day

Maternal NOAEL = 1000 mg/kg/day

LOAEL = not established.

Developmental NOAEL = 1000 mg/kg/day

LOAEL = not established.

870.3700a

Prenatal developmental (rat)

40874202, 41055903 (1988,

 1989)

 (Acceptable/Guideline)

0, 400, 800, 1200,

1600 mg/kg/day

Maternal NOAEL = 1600 mg/kg/day

LOAEL = not established.

Developmental NOAEL = 1200 mg/kg/day

LOAEL = 1600 mg/kg/day based on slightly

increased incidence of number of fetuses with

minor skeletal variations.

870.3700b

Prenatal developmental (rabbit)

00128721, 40985311 (1983,

1988)

Acceptable/Minimum

0, 100, 300, 1000 mg/kg/day

Maternal NOAEL = 1000 mg/kg/day

LOAEL = not established.

Developmental 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

mg/kg/day.

Parental/Reproductive/ Offspring LOAEL = 2405

mg/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 mg/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 mg/kg/day (HDT)

LOAEL = not established.

870.4200

Carcinogenicity (mouse)

00097886, 00098466 (1981)

(Acceptable/Guideline)

0, 1000, 3200, 10,000 ppm for

23 months mg/kg/day

NOAEL = 10,000 ppm (M: 1545 mg/kg/day; F:

1811 mg/kg/day)

LOAEL = not established.

No evidence of carcinogenicity

Cytogenetics

870.5375

Chromosome aberrations in vitro

 41147302 (1989) 

 (Acceptable/Guideline) Negative in the absence of S-9 at doses up to 4640

μg/ml in Chinese hamster 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/ml cultures at the 12- hour sampling, but not the 24-

hour sampling. There was a marked increase in osmotic

pressure at 10,000 μg/ml. The apparent positive results

in this assay are considered to be equivocal because of

the possible confounding effect of increased osmotic

pressure.

Cytogenetics ( in vivo)

 870.5385

41660001 (1990)

 (Acceptable/Guideline) Male and female B6C3F1 mice were given a single

intraperitoneal injection of the potassium salt of maleic

hydrazide at dose levels up to 1100 mg/kg, the level

causing death. There were no significant increases in

sister chromatid exchanges over control levels were

found in any treated male or female 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 (rec-) and strain H17 (rec+) of

Bacillus subtilis were treated with the potassium salt

of maleic hydrazide or technical grade maleic

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 maleic hydrazide or maleic hydrazide appear

to be recombinogenic, 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 chromatid

exchange assay in vitro

41147303 (1989)

(Acceptable/Guideline) The potassium salt of maleic hydrazide was tested in a

sister-chromatid exchange assay using Chinese

hamster ovary (CHO) cells in vitro at doses up to

10,000 μg/ml. Significant increases in sisterchromatid exchanges were observed in cultures both

without and with S-9 at cytotoxic doses of 10,000 

μg/ml without S-9 and 3200 and 10,000 μg/mL with

S-9.

870.6200a 

Acute 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 observations, motor activity, gross or neurohistopathological 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 adverse, 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

pharmacokinetics

(Rat)

41571701, 41679701,

 42432301 (1990) 

(Acceptable/Guideline)

Following oral or intravenous dosing of rats, maleic

hydrazide is excreted mainly in the urine (76-87% at 7

days) with lesser amounts in the feces (5-15%). Less

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

of bioaccumulation of radioactivity in any tissue or organ.

There were no differences between the sexes. Four-hour

urine contained mostly unchanged maleic hydrazide

(>60% of urinary radioactivity in males and >80% in

females) with a lesser amount of the sulfate conjugate of

maleic hydrazide. No other significant metabolites were

present in the urine. Fecal metabolites were not identified.
Page 17 of 19

Appendix II: Conservative Human Health Screening Level Cancer Assessment for 

Hydrazine Impurity in Maleic Hydrazide Technical Grade Products.

Maleic hydrazide technical grade products contain hydrazine as a contaminant and hydrazine has 

been associated with tumor induction. In 1982, at the close of the maleic hydrazide special 

review (then called Rebuttable Presumption Against Registration or RPAR), the Agency 

established an upper limit for hydrazine at 15 ppm in technical grade products containing maleic 

hydrazide. The Agency determined that, at this upper limit, there was no concern for hydrazine 

based 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 postapplication activities was estimated to be of lower risk. 

Highly 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 level 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 grade 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 number 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 currently 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 dispersible 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, 19713-25, 

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 technical grade products 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, inhalation 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. Tumors 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 for hydrazine is 3.0 (mg/kg/day)-1using the linearized 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 

IRIS website. 

Dietary Exposure/Risk Assessment

Reference: D420404, B. Cropp-Kohlligian, 6/12/14

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

assessments 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, (NHANES/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 parent 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 residues 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 

processing 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 treated 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 estimated 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 Q1* of 

3.0 (mg/kg/day)-1to the exposure, results in a screening level cancer risk estimate of 8 x 10-7. 

This estimate is considered conservative and does not underestimate risk. The major 

contributors were potatoes and potato chips. 
Residential and Occupational Exposure/Risk

Reference: D420405, S. Miller, 6/12/14

Screening level cancer risk estimates were calculated using a linear low-dose extrapolation 

approach in which a Lifetime Average Daily Dose (LADD) is first calculated and then compared 

with a Q1* that has been calculated for Hydrazine based on dose response data in the 

appropriate toxicology study (Q1* = 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 ADDs. LADDs were then calculated and compared to the 

Q1* 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) including long-sleeved shirt, long pants, chemical resistant gloves, shoes and 

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

scenarios (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 level cancer risk estimate of 5 x 

10-7.

Screening level occupational cancer 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 year for commercial 

applicators), and the label required restricted entry interval (REI) is 12 hours. It is assumed that 

handlers 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 2x 

10-5for private growers (growers applying pesticide to their own land) and 7 x 10-5 for 

commercial applicators. The screening level cancer 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, the estimated screening level 

cancer risk was 2 x 10-5for private handlers, and 7 x 10-5for commercial handlers. Estimated 

cancer risks from post-application activities were estimated to be of lower risk.