2

Table of Contents

EXECUTIVE SUMMARY ................................................................................................ 3

I. BACKGROUND ................................................................................................................ 9

II. INERT INGREDIENT PROFILE ...................................................................................... 9

A. Summary of Uses.................................................................................................... 9

B. Physical Chemical Properties ................................................................................. 9

III. HUMAN HEALTH ASSESSMENT................................................................................ 10

A. Summary of Toxicity Data.................................................................................... 10

B. Toxicity Endpoint Selection ................................................................................. 18

C. Special Considerations for Infants and Children .................................................. 19

IV. EXPOSURE ASSESSMENT ........................................................................................... 20

A. Dietary Exposure: ................................................................................................. 21

i. Acute exposure ...................................................................................................21

ii. Chronic exposure...............................................................................................21

iii. Cancer exposure ...............................................................................................23

B. Residential (Non-Occupational) Exposure: .......................................................... 23

i. From non-dietary exposure.................................................................................24

V. AGGREGATE RISK ASSESSMENT ............................................................................. 26

i. Acute Dietary Risk..............................................................................................26

ii. Chronic Dietary Risk. ........................................................................................26

iii. Aggregate Cancer Risk for U.S. Population.....................................................27

iv. Short-term Aggregate Risk. ..............................................................................27

v. Intermediate-Term Aggregate Risk. ..................................................................27

VI. OCCUPATIONAL EXPOSURE/RISK PATHWAY....................................................... 28

A. Occupational Handler Risk................................................................................... 28

B. Occupational Post-Application Risk..................................................................... 31

VII. CUMULATIVE EXPOSURE .......................................................................................... 33

VIII. ENVIRONMENTAL JUSTICE STATEMENT............................................................... 33

IX. ENVIRONMENTAL FATE CONSIDERATIONS ......................................................... 33

X. ECOTOXICITY................................................................................................................ 34

XI. RISK CHARACTERIZATION........................................................................................ 35

REFERENCES ............................................................................................................................. 39

APPENDIX................................................................................................................................... 43
3

EXECUTIVE SUMMARY

Exponent on behalf of Cheminova A/S. (1600 Wilson Boulevard, Suite 700, Arlington, 

VA 22209) is requesting that EPA to amend the established tolerance exemption from the 

requirement of a tolerance for maleic anhydride (CAS Reg. No. 108-31-6) to include use as an 

inert ingredient (stabilizer) in pesticide formulations applied to growing crops only in accordance 

with 40 CFR 180.920, at a maximum of 5% by weight in the pesticide formulation. 

Maleic anhydride is a multi-functional chemical intermediate with many industrial 

applications. The primary use of maleic anhydride is in the manufacture of polyester and alkyd 

resins. It is also used in the manufacture of lube oil additives, copolymers dye intermediates, 

pharmaceuticals, textile chemicals, fumaric and malic acid, and other organic compounds, and 

are approved for use as an indirect food additives by the U.S. Food and Drug Administration 

(FDA).

Maleic anhydride exhibits relatively low toxicity via oral and dermal routes of exposure. 

Maleic anhydride has been reported to be severely irritating to the skin and eyes of rabbits, 

dermally sensitizing to guinea pigs, and is a possible respiratory sensitizer.

In a six-month repeat dose inhalation study, CD rats, Engle hamsters, and Rhesus 

monkeys were exposed by inhalation (whole body) to 0, 1.1, 3.3 and 9.8 mg/m3(0, 0.3, 0.8, and 

2.4 ppm) maleic anhydride for six months. Body weights were decreased in rats at 3.3 and 9.8 

mg/m3(0.8, and 2.4 ppm) in the mid- and high-exposure groups at intervals during the study 

(<10%). However, at study termination, body weights were decreased only at the 9.8 mg/ m3

exposure group (6 – 8%). These decreases in the body weights are not considered as an adverse 

effect. All other effects were limited to the respiratory tract and eye. All of these effects were 

considered indicative of irritation and judged to be reversible. The NOAEL for irritation in this 

study was 3.3 mg/m3or 0.93 mg/kg/day based on localized eye/nasal irritation effects seen at the 

LOAEL of 9.8 mg/m3. The NOAEL for systemic toxicity in rats, hamsters and monkeys is 9.8 

mg/m3; the highest dose tested. 

In a 28-day inhalation study with maleic anhydride in Sprague-Dawley rats, evidence of 

nasal and ocular irritation (concentration-dependent) occurred at 12, 32 and 86 mg/m3. Reduced 

body weight gain and food consumption as well as increased incidence of hemorrhagic lung foci 

occurred at 32 and 86 mg/m3. The NOAEL for the systemic toxicity is 12 mg/m3(3 ppm) based 

on the reduced body weights and food consumption seen at the LOAEL of 32 mg/m3.

In a 90-day oral (dietary) study in rats were fed in the diet 0, 100, 250, or 600 mg/kg/day 

maleic anhydride for 90 days. At 600 mg/kg/day, there was slight proteinuria in both sexes, 

increased relative liver weight in males, increased relative/absolute kidney weights in both sexes. 

Macroscopic and microscopic kidney changes, including nephrosis were seen in male rats at 100, 

250, and 600 mg/kg/day. The LOAEL for this study is 100 mg/kg/day. In a separate study rats 

were fed in the diet 0, 20, or 40 mg/kg /day maleic anhydride, seven days a week for 90 days. 

There were no treatment-related effects. The NOAEL for this study is 40 mg/kg/day.
4

In a 183-day oral (dietary) study in rats there were renal lesions and an increase in the 

absolute and relative liver and kidney weights at 250 mg/kg/day and 600 mg/kg/day. The 

LOAEL for this study is 250 mg/kg/day. A NOAEL was not established.

In a 2-year oral (dietary) study in rats only marginal toxicity was observed which was 

evidenced by small (<6%), but dose-related, decrease in body weights of rats. The LOAEL for 

this study is 32 mg/kg/day and the NOAEL for this study is 10 mg/kg/day.

In a 90-day dietary study in dogs, there were no treatment related effects observed at 

doses up to 60 mg/kg/day, the highest dose tested.

In an oral (gavage) developmental toxicity study in CD rats, no treatment related adverse 

effects were observed. The NOAEL for both maternal and developmental toxicity was 140 

mg/kg/day, the highest dose tested.

In a two-generation oral (gavage) reproductive toxicity study in rats, significant mortality 

occurred in the F0 and F1 parental animals and maleic anhydride was toxic to parental animals in 

all dose groups (20, 55 and 150 mg/kg/day of maleic anhydride). There was no significant 

reduction in the percentage of pregnant females or the percentage of fertile males. Adverse 

effects on litter size and on pup survival were observed at the dose of 55 mg/kg/day and above in 

the F2 litters. Maleic anhydride was toxic to parental animals in all dose groups. For parental 

toxicity the LOAEL was 20 mg/kg/day. A NOAEL for parental toxicity was not established. The 

NOAEL for offspring toxicity was 55 mg/kg/day based on decreased pup survival observed at 

150 mg/kg/day.

Maleic anhydride was negative for mutagenicity or chromosomal aberrations in a battery 

of tests of genotoxicity including a bacterial gene mutation test, an in vivo mammalian 

chromosomal aberration test using rat bone marrow and an in vitro chromosomal test.

In the previously described 2-year dietary study, male and female rats were exposed to 0, 

10, 32, or 100 mg/kg/day maleic anhydride in feed for two years. There were no increases in 

tumor incidence that were considered related to maleic anhydride exposure. Additionally in a 

two-year chronic feeding study on Osborne-Mendel rats fed 0, 0.5, 1.0 or 1.5% maleic acid in 

their diets for two years resulted in no treatment-related increases in tumors. 

A 1-hour neurotoxicity inhalation study exposed rats to 0.72 mg/L of maleic acid which 

produced generalized inactivity, hyperpnea and sedation within 15 minutes of exposure. Gross

necropsy revealed no significant findings. However, no neurotoxic effects have been reported in 

the available studies.

No immunotoxicity studies on maleic anhydride or maleic acid were available in the 

database. 

In a metabolism study, dogs were fed 60 mg/kg/day maleic anhydride for 90 days. Using 

a one compartment model, uptake rate and elimination rate constants were calculated as 3.49 x 

10-3per day and 8.32 x 10-2per day, respectively. Based on this model, 99% of steady state was 

reached by day 55 of the study. 
5

Maleic anhydride is readily hydrolyzed to maleic acid under aqueous conditions. It is 

then hydroxylated to malic acid, which participates in the Krebs cycle or may be excreted 

unchanged or in conjugated form. 

Although no dermal absorption studies were available for maleic anhydride or maleic 

acid, a dermal absorption value was estimated using the ratio of an oral LD50 and a dermal LD50. 

The two studies used were the oral rabbit LD50 of 875 mg/kg and the dermal rabbit LD50 of 2620 

mg/kg maleic anhydride. The resulting estimated dermal absorption was 33%. 

The chronic reference dose (cRfD) of 0.1 mg/kg/day was determined on the basis of the 

NOAEL of 10 mg/kg/day from the 2-year oral toxicity study in rats. The LOAEL of 32

mg/kg/day is based on slight to marginal decreases in bodyweight. This endpoint was used for 

dietary and dermal exposures. The 6-month inhalation toxicity study with a NOAEL of 0.93 

mg/kg/day is used for inhalation exposures. The LOAEL of 1000 mg/kg/day is based on 

reduction in bodyweights and hyperplastic and metaplastic changes of nasal tissues. These 

studies provided the lowest NOAEL in the database (most sensitive endpoint) and also provides

the most protective limits for potential human effects. An uncertainty factor (UF) of 100X (10-

fold for interspecies extrapolation and 10-fold for intra species variability) was applied to the 

NOAELs of 10 and 0.93 mg/kg/day to derive the cRfD for oral, dermal and inhalation exposure. 

This endpoint of concern was also used for all dermal and inhalation exposure scenarios. Dermal 

absorption was estimated to be 33%. The limit in formulation was reduced from 5% to 3.5% as 

requested by Exponent.

EPA has determined that reliable data show the safety of infants and children would be 

adequately protected if the FQPA SF were reduced to 1X. 

An acute dietary risk assessment was not conducted because no endpoint of concern 

following a single exposure was identified in the available studies. A chronic dietary exposure 

assessment was completed and performed using the Dietary Exposure Evaluation Model DEEMFCIDTM, Version 3.16. The chronic population-adjusted dose (cPAD) 0.1 mg/kg/day.

Based on analyses of estimated dietary risks for the general U.S. population and various 

population subgroups, the chronic dietary exposure estimates for maleic anhydride are below the 

Agency’s level of concern for the general U.S. population and all population subgroups. The 

chronic dietary exposure estimate is 15.9% of the cPAD for the general population and 72.4% of 

the cPAD for the highest exposed population subgroup, children 1-2 years old.

The Agency’s level of concern (LOC) for occupational and residential dermal and 

inhalation exposures to maleic anhydride is 100 [i.e., a margin of exposure (MOE) greater than 

100 is not of concern to EPA]. The LOC is based on a 10X uncertainty factor (UF) to account 

for interspecies extrapolation to humans from the animal test species and 10X UF to account for 

intra-species sensitivity.

Outdoor residential applicator exposures were calculated using three exposure scenarios, 

low pressure handwand, hose end sprayer and trigger sprayer were assessed for each pesticide 
6

type, herbicide, insecticide and fungicide in both short- and intermediate-term scenarios. The 

combined outdoor residential applicator dermal and inhalation MOEs ranged from 280 to 1300. 

As the level of concern is for MOEs that are lower than 100, these MOEs are not of concern. 

Indoor residential applicator exposures were calculated using three exposure scenarios, 

mopping, wiping and aerosol spray were assessed in both short- and intermediate-term scenarios. 

The combined indoor residential applicator dermal and inhalation MOEs ranged from 97 to 

3600. The level of concern is for MOEs that are lower than 100. The MOE of 97 for indoor 

surface cleaner wiping is lower than the level of concern and is the only MOE to be below 100. 

However with all the conservatisms incorporated into this exposure estimate, this scenario is not 

expected to be of concern.

Post-application residential exposure to treated lawns was calculated to be 950 and 1900 

for adult short- and intermediate-term exposures respectively and 490 and 990 for children shortand intermediate-term exposures respectively. The post-application child (hand-to-mouth) shortterm MOE was calculated to be 4200 from treated lawns. As the level of concern is for MOEs 

that are lower than 100, these MOEs are not of concern.

Short-term aggregate exposure takes into account short-term residential exposure plus 

chronic exposure to food and water (considered to be a background exposure level). Maleic 

anhydride may be used as an inert ingredient in pesticide products that could result in short-term 

residential exposure. The Agency has determined that it is appropriate to aggregate chronic 

exposure through food and water with short-term residential exposures. Using the exposure 

assumptions described in Section IV, EPA has calculated the combined short-term aggregated 

food, water, and residential exposures. The adult short-term aggregate MOE was calculated to be 

112 for both males and females. Adult aggregate MOE combines average food and water 

exposure from the chronic dietary exposure with high end residential applicator exposure (liquid 

trigger sprayer). As the level of concern is for MOEs that are lower than 100, this MOE is not of 

concern. EPA has concluded the combined short-term aggregated food, water, and residential 

exposures results in an aggregate MOE of 105 for children. Children’s aggregate MOE combines 

average food and water exposure from the chronic dietary exposure with residential exposure 

associated with contact with treated lawns (post-app dermal exposure + hand-to-mouth + objectto-mouth). As the level of concern is for MOEs that are lower than 100, these MOEs are not of 

concern.

Intermediate -term aggregate exposure takes into account intermediate-term residential 

exposure plus chronic exposure to food and water (considered to be a background exposure 

level). Maleic anhydride may be used as an inert ingredient in pesticide products that could result 

in intermediate-term residential exposure. The Agency has determined that it is appropriate to 

aggregate chronic exposure through food and water with intermediate-term residential exposures. 

Using the exposure assumptions described in Section IV, EPA has calculated the combined 

intermediate-term aggregated food, water, and residential exposures. The adult intermediate-term 

aggregate MOE was calculated to be 178 for both males and females. Adult aggregate MOE 

combines average food and water exposure from the chronic dietary exposure with high end 

residential applicator exposure (liquid trigger sprayer). As the level of concern is for MOEs that 

are lower than 100, this MOE is not of concern. EPA has concluded the combined intermediate-
7

term aggregated food, water, and residential exposures results in an aggregate MOE of 119 for 

children. Children’s aggregate MOE combines average food and water exposure from the 

chronic dietary exposure with residential exposure associated with contact with treated lawns 

(post-app dermal exposure + hand-to-mouth + object-to-mouth). As the level of concern is for 

MOEs that are lower than 100, these MOEs are not of concern.

Occupational handler risks are not of concern for all scenarios. It is noted that this

occupational handler assessment assumes that mixer/loader/applicators are wearing gloves and 

not wearing protective respirators when using open pour loading in support of aerial and 

groundboom application. The combined occupational handler combined dermal and inhalation 

MOEs ranged from 460 to 4500. The estimated MOEs are greater than 100 therefore the 

occupational MOEs are not of concern. 

Occupational post-application risks are not of concern for all scenarios. It is noted that 

this occupational post-application assessment assumes default 20% dislodgeable foliar residue. 

The estimated MOEs are greater than 100 based. The lowest estimated MOE was 110, based on 

hand harvesting, leaf pulling, thinning, pruning, training/tying grapes. As the level of concern is 

for MOEs that are lower than 100, these MOEs are not of concern.

Maleic anhydride is not persistent in the environment and is not expected to

bioaccumulate. In the presence of water, maleic anhydride rapidly hydrolyzes to form maleic 

acid. The half-life of maleic anhydride in air is estimated to be 4.2 to 16 hours; due primarily to 

direct reactions with photochemically generated hydroxyl radicals. Maleic anhydride and maleic 

acid are readily biodegraded under aerobic conditions in sewage sludge, and are expected to 

biodegrade in soil and water as well. Fugacity-based fate and transport modelling suggest that 

maleic anhydride, hydrolyzed to maleic acid in water and under humid conditions, will partition 

primarily to water. 

Based on the low toxicity to fish, trout (Salmo gairdneri) and bluegill (Lepomis 

macrochirus), freshwater aquatic invertebrate, Daphnia magna, and the lack of inhibition on 

growth of the unicellular algae, Pseudokirchneriella subcapitata, effects of concern to nontarget 

aquatic species resulting from the use of maleic anhydride as an inert ingredient is not 

anticipated. 

Potential areas of environmental justice concerns, to the extent possible, were considered 

in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal 

Actions to Address Environmental Justice in Minority Populations and Low-Income 

Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.

Taking into consideration all available information on maleic anhydride EPA concludes 

that there is a reasonable certainty that no harm to any population subgroup will result from 

aggregate exposure to maleic anhydride when considering residential, occupational, dietary 

exposure and all other non-occupational sources of pesticide exposure for which there is reliable 

information. Therefore, the establishment of an exemption from the requirement of a tolerance 

under 40 CFR 180.920 for residues of maleic anhydride (CAS Reg. No. 108-31-6) when used as
8

a pesticide inert ingredient (stabilizer) applied to growing crops at a maximum of 3.5% in 

pesticide formulations can be considered safe under section 408(q) of the FFDCA.
9

I. BACKGROUND

Exponent on behalf of Cheminova A/S. (1600 Wilson Boulevard, Suite 700, Arlington, 

VA 22209) is requesting that EPA establish an exemption from tolerance for maleic anhydride

(CAS Reg. No. 108-31-6) when used as (stabilizer) in pesticide formulations applied to growing 

crops in accordance with 40 CFR 180.920 and a maximum of 3.5% in the pesticide formulation. 

II. INERT INGREDIENT PROFILE

A. Summary of Uses

Maleic anhydride and maleic acid are multi-functional chemical intermediates with many 

industrial applications. The primary use of maleic anhydride is in the manufacture of 

polyester and alkyd resins. It is also used in the manufacture of lube oil additives, 

copolymers dye intermediates, pharmaceuticals, textile chemicals, fumaric and malic 

acid, and other organic compounds. Maleic acid is an intermediate in the production of 

maleic anhydride. While not as important economically as the anhydride, which is easier 

to use, maleic acid is used in the manufacture of alkyd and polyester resins, surface 

coatings, lubricant additives, plasticizers, copolymers, and textile chemicals. Both 

chemicals are approved for use as “indirect” food additives by the U.S. Food and Drug 

Administration (FDA).

B. Physical Chemical Properties

Table 1. Physical and Chemical Properties of Maleic Anhydride and Maleic Acid

Parameter Maleic Anhydride Maleic Acid Reference

Structure ChemFinder 

2006

CAS # 108-31-6 110-16-7 HSDB 2006

Molecular Formula C4H2O3 C4H4O4

Molecular Weight (g/mol) 98.06 116.07

Common Names

Melting Point (°C) 52.8 138-139

Boiling Point (°C) 202 @ 760 mm HG 135

Water Solubility (at 25°C) Soluble, forming maleic 

acid (491 mg/L)* Extremely soluble (788 g/L)

Other Solubility Soluble in ether, acetate, 

and chloroform

Soluble in alcohol, acetone, 

and glacial acetic acid

Octanol/water Partition 

Coefficient (Log Kow)

1.62* -0.48

Soil organic carbon/water 

Partition coefficient (Koc) 1* N/A

Specific Gravity (at 20°C) 1.48 1.59

Vapor Pressure (mmHg at 25°C) 2.5 x 10-1 3.59 x 10-5*

Henry's Law Constant

(atm*m3/mole at 25°C) 3.93 x 10-6 * 7x10-14 

*Extrapolated/Estimated
III. HUMAN HEALTH ASSESSMENT

A. Summary of Toxicity Data 

Acute Oral and Dermal Toxicity

Maleic anhydride and maleic acid exhibit relatively low order of toxicity by the oral and 

dermal routes of exposure. See summaries in table below.

Inhalation Toxicity

No available.

Primary Eye Irritation

Maleic anhydride is severely irritating to the eyes of rabbits. The eye irritation score was 

106.7 (out of a maximum of 110). The mean conjunctival erythema scores at 24 and 48 

hours were 3.8 and 3.8 respectively. The iridial lesions scores at 24 and 48 hours were 2.0 

and 2.0, respectively. The study was terminated at the 48-hour post dosing time point.

Primary Skin Irritation

Maleic anhydride was severely irritating to the skin of rabbits after application of 0.5 g to 

the skin for 4 hours. The mean irritation scores for erythema and edema ranged from 3.67 

to 4.00 throughout the 7-day observation period (OECD SIDS 2004). 

Application of 500 mg maleic acid for 24 hours produced mild skin irritation in the rabbit 

and moderate irritation in the guinea pig. No further information was given. The studies 

on maleic acid are taken from the secondary literature, which references the results from 

unpublished reports. The irritation of maleic anhydride has shown to change from nonirritating when as applied as a finely ground powder to severely irritating skin when 

moistened with water, indicating hydrolysis of maleic anhydride to maleic acid through 

an exothermic reaction.

Dermal Sensitization

Maleic anhydride has been shown to be a skins sensitizer to guinea pigs using the 

Buehler method. Maleic anhydride has also been tested for potential respiratory

sensitization in Sprague-Dawley rats. Maleic anhydride exposed and challenged rats had 

a slight, but significant, increase in maleic anhydride-specific serum IgG antibody levels 

compared to non-exposed control animals. However, other prominent features of acid 

anhydride respiratory sensitization reactions in the rat model such as increased 

hemorrhagic lung foci, increased lung weight and volume, and extensive lung pathology 

did not occur. Since there are no general validated rat models for respiratory 

sensitization, the significance of the increased IgG antibodies (in the absence of lung 

pathology) is unclear with respect to any potentially sensitizing properties.
11

No data exists for maleic acid. However, unlike maleic anhydride, maleic acid is not 

expected to form haptens by acylating with amino acids, resulting in an immunological 

response (dermal or respiratory sensitization).

Acute Toxicity

Table 2. Acute Toxicity Profile of Maleic Anhydride and Maleic Acid

Study Type Results MRIDs # /Reference

Acute Oral – rat, mouse, rabbit guinea 

pig

LD50 (rat) = 400 to 1050 mg/kg

LD50 (mouse) = 465mg/kg

LD50 (rabbit) = 875 mg/kg

LD50 (guinea pig) = 390 mg/kg

OECD SIDS 2004

HSDB 2006

(Lewis et al. 1996)

Acute Dermal – rabbit LD50 (rabbit) = 1600 mg/kg maleic acid

LD50 (rabbit) = 2600 mg/kg maleic 

anhydride

OECD SIDS 2004

(Eastman Kodak 1969)

(Vernot et al. 1977)

Acute Inhalation N/A N/A

Primary Eye Irritation – rabbit Severely Irritating OECD SIDS 2004

Primary Skin Irritation – rabbit Severely Irritating OECD SIDS 2004

Dermal Sensitization – guinea pig Maleic Anhydride: Skin sensitizer

Maleic Acid: not predicted to be skin 

sensitizer

OECD SIDS 2004

Respiratory Sensitization - rat Maleic Anhydride: possible respiratory 

sensitizer

Maleic Acid: not predicted to be 

respiratory sensitizer

OECD SIDS 2004

Repeat Dose Toxicity –

In a repeat dose inhalation study, CD rats, Engle hamsters, and Rhesus monkeys were 

exposed by inhalation (whole body) to 0, 1.1, 3.3 and 9.8 mg/m3(0, 0.3, 0.8, and 2.4 

ppm) maleic anhydride for six hours/day, five days/week for six months. Body weights 

were decreased in rats in the mid- and high-exposure groups at intervals during the study 

(<10%). However, at study termination, body weights were decreased only in the highexposure group (6 – 8%). All other effects were limited to the respiratory tract and eye. In 

the high-exposure groups, nasal discharge, ocular irritation, and slight dyspnea with 

coughing and sneezing were observed. The effects were less severe in the animals from 

the mid- and low-exposure groups. In the rats and hamsters (but not monkeys), 

hyperplastic changes in the nasal tissues were present in the mid- and high-exposure 

groups only. Also in the rats and hamsters, metaplastic changes in the nasal tissues were 

present in all exposure groups. In all species, there was some mucosal and/or submucosal 

infiltration of neutrophils into the nasal tissues at all exposure groups. All of these effects 

were considered indicative of irritation and judged to be reversible. The NOAEL for 

irritation in this study was 3.3 mg/m3or 0.93 mg/kg/day based on localized eye/nasal 

irritation effects seen at the LOAEL of 9.9 mg/m3. The NOAEL for systemic toxicity in 

rats, hamsters and monkeys is 9.8 mg/m3, the highest dose tested. (Short et al., 1988).
12

In another repeat dose inhalation study, male and female Sprague-Dawley rats were 

exposed by inhalation (whole body) to 0, 12, 32, or 86 mg/m3(0, 3, 8, or 21 ppm) maleic 

anhydride, six hours/day, five days/week for four weeks. Evidence of nasal and ocular 

irritation (concentration-dependent) occurred at all treatment levels. At the highest 

concentration, ocular and nasal discharge, periodic nasal bleeding and respiratory distress

were seen. Less severe effects occurred at lower concentrations. Reduced body weight 

gain (both sexes) and food consumption (females only) occurred at 32 and 86 mg/m3. 

There were no hematological, clinical chemistry or urine changes that could be 

conclusively attributed to treatment. There was increased incidence of hemorrhagic lung 

foci in the mid- and high-exposure groups compared to controls. There were also 

treatment-related effects (concentration-related) in the nasal turbinates, trachea and lungs. 

These included epithelial hyperplasia and presence of inflammatory exudate in the nasal 

turbinates and trachea, and in the lungs, epithelial hyperplasia, squamous metaplasia and 

intra-alveolar hemorrhage. The severities of the microscopic changes were generally

described as slight-to-moderate. Also, keratitis or corneal vascularization was noted in 

the eyes of a number of animals from the high-dose group, which was considered by the 

authors to be a local effect and not a reflection of systemic toxicity (Goldenthal, 1979a). 

The LOAEL for this study is 12 mg/m3(3 ppm).

In a 90-day repeat dose dietary study, male and female rats were fed in the diet 0, 100, 

250, or 600 mg/kg/day maleic anhydride, seven days a week for 90 days. At 600 

mg/kg/day, there was slight proteinuria in both sexes, increased relative liver weight in 

males, increased relative/absolute kidney weights in both sexes. At 250 mg/kg/day, there 

were increased relative/absolute kidney weights in males. Grossly observed kidney 

changes were seen in males fed maleic anhydride 100, 250, and 600 mg/kg/day. The

changes were characterized by increased size, pale discoloration, and evidence of dilated 

tubules in the cortex. Microscopically, the kidneys showed varying degrees of nephrosis, 

being most severe in the high-dose group. These changes consisted of diffuse tubular 

dilatation, hypertrophy, and degeneration and regeneration of the tubular cells in the 

cortical portion of the nephron. A decrease in severity of these changes was observed at 

lower dose levels, with the kidneys from the 100 mg/kg dose group showing minimal 

alterations. Similar changes were observed in the kidneys of females, but were generally 

limited to the high-dose group and were much less severe (Humiston et al., 1975a). The 

LOAEL for this study is 100 mg/kg/day. In a separate study that was included in the 

same report by Humiston et al. (1975a), male and female rats were fed in the diet 0, 20, 

or 40 mg/kg /day maleic anhydride, seven days a week for 90 days. There were no 

treatment-related effects. The NOAEL for this study is 40 mg/kg/day.

In another repeat dose dietary study, male rats were fed 0, 250, or 600 mg/kg/day maleic 

anhydride in the diet for 183 days, there was a significant increase in the absolute and 

relative liver and kidney weights for both treatment groups, increased relative testes 

weight, brain and heart, and decreased fasted body weights for rats at 600 mg/kg/day. 

Treatment-related changes were present in the kidneys of rats terminated at 90 and 183

days. The observed changes indicated a marked accentuation of the spontaneously 

occurring findings seen in the control animals. The changes in the controls and treated 

animals included: individual tubules that were dilated and contained eosinophilic staining 
13

casts, granular degeneration of the epithelial cells lining these tubules, tubular collapse 

and atrophy with peritubular fibrosis, focal mononuclear inflammatory cell infiltrates, 

glomeruli that showed thickening of the basement membrane, thickening and 

epithelialization of Bowman’s Capsule, and occasionally showed either focal or diffuse 

sclerosis of the glomerular tufts. Both tubular and glomerular changes in treated animals 

were more severe than controls, and much more severe in the treated rats at 183 days

compared to 90 days. In addition to the focal nature of the lesion (in controls), the tubules

throughout the cortex of treated rats showed a generalized dilatation and hypertrophy. 

There were more degenerative tubules and tubules showing mitotic activity in treated 

versus controls. The degree of degenerative, hypertrophic, and regenerative changes was 

dose-related. In many of the 600 mg/kg dose group animals, there was a marked decrease 

in the amount of functional tissue in the kidney. Livers of maleic anhydride-treated rats at 

183 days showed changes characterized by swollen individual hepatocytes having 

vacuolated cytoplasm (Humiston and Quast, 1977). The LOAEL for this study is 250 

mg/kg/day.

In a 2-year dietary study, male and female rats were exposed to 0, 10, 32, or 100 

mg/kg/day maleic anhydride in feed, seven days a week for two years. There was only 

marginal toxicity, which was evidenced by small (<6%), but dose-related, decrease in 

body weights of male rats fed 32 and 100 mg/kg/day compared to the controls. The 

female rats fed 32 and 100 mg/kg/day also had reduced body weights, but the reductions 

were smaller and of shorter duration than those observed in males. Food consumption

was also slightly reduced during limited periods during the study for animals in the midand high dose groups. Neither neurologic nor ophthalmologic evaluations revealed 

differences between treated and control animals. There was a high incidence of cataracts 

in the animals of this study, with 100% of the animals examined at 18 month and at study 

termination bearing cataracts. The severity of these cataracts was independent of maleic 

anhydride consumption. Hematology, clinical chemistry, gross or histopathological 

evaluations (including the kidneys) showed no differences between treated and control 

animals that were considered related to maleic anhydride exposure. (CIIT, 1983.) The 

NOAEL for this study is 10 mg/kg/day.

In a 90-day dietary study, dogs were fed in the diet 0, 20, 40, or 60 mg maleic 

anhydride/kg/day, seven days a week for 90 days. Food intake was decreased for the first 

few weeks in both sexes of dogs receiving 60 mg/kg/day. No other changes were 

observed that were considered related to the ingestion of diets containing maleic 

anhydride (Humiston et al., 1975b). Since the changes in food intake were transient and 

did not result in long-term or terminal body weight effects, the NOAEL was determined 

to be 60 mg/kg/day.

Developmental Toxicity -

In female CD rats dosed orally (by gavage) to 0, 30, 90 or 140 mg/kg maleic anhydride in 

corn oil during days 6 to 15 of gestation had no developmental effects that were 

considered treatment related. One adult female died in each experimental group. Dams in 

all experimental groups either failed to gain weight or lost weight between Days 6 and 9 

of gestation; however, the effect was reversible and there were no statistically significant 
14

effects on body weight gains at any interval. Dams from all test groups produced normalsized litters, with no evidence of post-implantation loss. Fetal body weights in all 

treatment groups were slightly reduced compared to controls but the reductions were 

statistically significant only in the 30 and 90 mg/kg groups. This is not considered to be 

compound-related because fetal weights for concurrent control and all treated groups 

were slightly greater than the historical control values. Malformations were observed in 

one fetus (1/23 litters) from the control group, two fetuses (2/23 litters) from the 30 

mg/kg group and three fetuses (3/21 litters) from the 140 mg/kg group. There was no 

evidence of a dose-related increase in any specific malformation. Fetal variations were 

comparable both in type and frequency in the control and treated groups. There was, 

however, no maternal NOEL because females at 30 mg/kg failed to gain weight from 

gestation day 6-9 although this was not statistically significant. The NOAEL for both 

maternal and developmental toxicity was 140 mg/kg/day (Goldenthal et al, 1979b; Short 

et al., 1986). These effects are likely to reflect the toxicity of maleic acid since maleic 

anhydride is rapidly hydrolyzed to maleic acid in the body, particularly by the oral route 

of exposure.

Reproductive Toxicity

Maleic anhydride has been tested in a two-generation reproductive toxicity study at oral 

gavage doses of 0, 20, 55 and 150 mg/kg/day. There was no significant reduction in the 

percentage of pregnant females or the percentage of fertile males. No adverse effects on 

litter size and on pup survival were observed at doses up to 150 mg/kg/day in the F1

litters or up to 55 mg/kg/day in the F2 litters. Maleic anhydride was toxic to parental 

animals in all dose groups. Significant mortality occurred in the F0 and F1 parental 

animals. During the second generation, the 150 mg/kg/day female group was terminated 

on study week 42 due to 100% mortality. It was decided to terminate the 150 mg/kg/day 

group males at week 44 due to no females being available for mating. Respiratory rales 

were observed in the F1 (and to minor extent in the F0) adults and the incidence and 

severity appeared to increase with dose. In the high-dose group F0 body weights were

significantly reduced by Week 11, this reduction persisted for the remainder of the test. 

The middose group means were low but not statistically significantly different from the 

controls. F1 generation showed a similar pattern of depressed weight gain; however, only 

the F1 males in the high-dose group had statistically significant body weight depression at 

30 weeks. Microscopic examination of tissues for F0 adults revealed compound-related 

changes in the kidneys and bladder of rats in all dose groups. However, renal cortical 

necrosis, present in 60% of the males and in 15% of the females was only observed in the 

high-dose F0 group. In the F1 generation, the absolute kidney weights of adult females in 

the low- and mid-exposure groups were significantly increased to 108 and 111%, 

respectively, of the control value. There were no microscopic changes in these kidneys. 

For parental toxicity, however, the LOAEL was 20 mg/kg/day. A NOAEL for parental 

toxicity was not established. The NOAEL for offspring toxicity was 55 mg/kg/day based 

on decreased pup survival observed at 150 mg/kg/day. (IRDC, 1982; Short et al., 1986.)

These effects are likely to reflect the toxicity of maleic acid since maleic anhydride is 

rapidly hydrolyzed to maleic acid in the body, particularly by the oral route of exposure.

Mutagenicity and Genotoxicity
15

Three Salmonella typhimurium/mammalian microsomal (Ames) assays and one Bacillus 

subtillis recombination assay with and without activation were all negative (Haworth et 

al., 1983; Ishidate and Yoshikawa, 1980; Ishidate et al., 1981; Kawachi et al., 1980; 

Bearman, 1990; Hüls AG (1988a).

A Salmonella typhimurium/mammalian microsomal (Ames) assay with and without 

activation was negative (Lake et al., 1988).

Maleic anhydride has been reported to increase chromosomal aberrations in Chinese 

hamster lung fibroblast cells with and without metabolic activation (Ishidate and 

Yoshikawa, 1980; Ishidate et al., 1981; Kowachi et al., 1980). Maleic anhydride is known 

to hydrolyze to maleic acid in aqueous media. Due to inadequate documentation on this 

study, it is unclear whether the results were due to the test material itself or a change in 

pH to an acidic environment, which could have resulted in a nonspecific effect.

Exposure of Sprague-Dawley rats to 0, 1, or 100 mg/m3 (0, 0.25 and 25 ppm) maleic 

anhydride did not increase chromosomal aberrations in the bone marrow (Hazleton 

Laboratories America, Inc., 1983). These results likely reflect the toxicity of maleic acid, 

as well as maleic anhydride, since maleic anhydride is rapidly hydrolyzed to maleic acid 

in the body.

Carcinogenicity

In the previously described 2-year dietary study, male and female rats were exposed to 0, 

10, 32, or 100 mg/kg/day maleic anhydride in feed, seven days a week for two years. 

There was only marginal toxicity, which was evidenced by small (<6%), but dose-related, 

decrease in body weights of male rats fed 32 and 100 mg/kg/day compared to the 

controls. The female rats fed 32 and 100 mg/kg/day also had reduced body weights, but 

the reductions were smaller and of shorter duration than those observed in males. Food 

consumption was also slightly reduced during limited periods during the study for 

animals in the mid- and high dose groups. There were no increases in tumor incidence 

that were considered related to maleic anhydride exposure. There was an unusually high 

incidence of uterine adenocarcinomas in this study. These lesions were present in similar 

numbers in control and treated animals (23/86 and 20/82, respectively). The report stated 

that “Uterine adenocarcinomas is not a common spontaneous lesion in this strain of rats,” 

although no historical control data was provided. It is unclear why the incidence of 

uterine adenocarcinomas was high in this particular study both in the controls and the 

treated animals. But, it does not appear to be related to exposure to maleic anhydride. The 

authors speculated that this may have been related to altered hormonal status caused by 

the continuous light exposure since there were problems with the animal room lighting

control system which resulted in exposure to continuous light for an unknown period 

(CIIT, 1983).

In a two-year chronic feeding study, Osborne-Mendel rats were fed 0, 0.5, 1.0, or 1.5% 

(0, 5000, 10000 and 15000 ppm) maleic acid in their diets for two years. These 

concentrations can be approximated to correspond with doses of (0, 250, 500 and 750 

mg/kg/day) assuming a 0.4 kg rat eats 20g food/day. Concentrations of 1.0 and 1.5% 
16

maleic acid retarded the growth rate of rats and all concentrations of maleic acid 

increased mortality rate. However, no treatment-related increase in tumors was reported 

(Fitzhugh and Nelson, 1947).

Immunotoxicity

No immunotoxicity studies were available in the database for maleic anhydride or maleic 

acid.

Neurotoxicity

A 1-hour inhalation exposure of rats to 0.72 mg/L of maleic acid produced generalized 

inactivity, hyperpnea and sedation within 15 minutes of exposure (HSDB, 2006). Gross 

necropsy revealed no significant findings. However, no neurotoxic effects have been 

reported in the available studies.

Metabolism and Pharmacokinetics

Maleic anhydride is readily hydrolyzed to maleic acid under aqueous conditions. Then it 

is hydroxylated to malic acid, which participates in the krebs cycle or may be excreted 

unchanged or in conjugated form. Maleic acid is an antimetabolite of fumaric acid 

(IUCLID). Maleic anhydride also has the potential to form haptens by acrylating with 

amino acids, resulting in an immunological response (dermal and respiratory sensitization 

(OECD SIDS 2004). 

In a metabolism study, dogs were fed 60 mg/kg/day maleic anhydride for 90 days. Using 

a one compartment model, uptake rate and elimination rate constants were calculated as 

3.49 x 10-3 per day and 8.32 x 10-2 per day, respectively. Based on this model, 99% of 

steady state was reached by day 55 of the study. (HSDB 2006)

Dermal Absorption

Although no dermal absorption studies were available for maleic anhydride or maleic 

acid, a dermal absorption value was estimated using the ratio of an oral LD50 and a 

dermal LD50. The two studies used were the oral rabbit LD50 of 875 mg/kg and the 

dermal rabbit LD50 of 2620 mg/kg. The resulting estimated dermal absorption was 33%. 

Table 3. Toxicology Profile of maleic acid and anhydride

Guideline No./ 

Study Type

Doses Levels Results MRID No. 

(year)/References

4-week inhalationrats

Maleic anhydride

0, 12, 32 or 84

mg/m3

(0, 3, 8 or 21 

ppm)

NOAEL N/A

LOAEL 12 mg/m3 based on epithelial 

hyperplasia, inflammatory exudates in nasal 

turbinates and trachea and epithelia 

pyerplasia, squamous metaplasia, and intraalveolar hemorrhage in lung

OECD SIDS 2004

Goldenthal, 1979a
17

Table 3. Toxicology Profile of maleic acid and anhydride

Guideline No./ 

Study Type

Doses Levels Results MRID No. 

(year)/References

6-month inhalation –

rats, hamsters, 

monkey

Maleic anhydride

0, 1.1, 3.3 or 9.8 

mg/m3

(0, 0.3, 0.8 or 

2.4 ppm)

NOAEL (irritation) 3.3 mg/m3 or 0.93 

mg/kg/day for rats, hamsters and monkeys

LOAEL (irritation) 9.8 mg/m3 based on 

localized eye/nasal irritation

NOAEL (systemic) 9.8 mg/m3 highest dosed 

tested

LOAEL (systemic) N/A

OECD SIDS 2004

HSDB 2006

Short et al., 1988

90-day oral (diet) –

rats

Maleic anhydride

0, 100, 250 or 

600 mg/kg/day

LOAEL 100 mg/kg/day based on kidney 

effects which were more severe in males than 

females. Effects seen in tubular cells and 

glomeruli. Kidney effects due to maleic acid 

(known to cause kidney damage).

OECD SIDS 2004

Humiston et al., 

1975a

2-year oral study –

rats

Maleic anhydride

0, 10, 32 or 100 

mg/kg/day

NOAEL 10 mg/kg/day.

LOAEL 32 mg/kg/day based on slight to 

marginal decreases in bodyweight.

OECD SIDS 2004

EPA IRIS 2006

CIIT, 1983

90-day dietary study 

– dogs

Maleic anhydride

0, 20, 40 or 60 

mg/kg/day

NOAEL 40 mg/kg/day

LOAEL 60 mg/kg/day based on 

hematological effects, no kidney effects

OECD SIDS 2004

EPA IRIS 2006

Humiston et al., 

1975b

2-gen Reproductive 

study (gavage) – rats

Maleic anhydride

0, 20, 55 or 150 

mg/kg/day

NOAEL offspring 55 mg/kg/day 

LOAEL offspring 150 mg/kg/day based on 

decreased pup survival

NOAEL parental N/A

LOAEL parental 20 mg/kg/day based on 

histopathological effects in kidney and bladder 

of first gen parental animals.

OECD SIDS 2004

HSDB 2006

IRDC, 1982 Short et 

al., 1986

12-week Tetratogenic

study (gavage) –

female rats

Maleic anhydride

0, 30, 90 or 140 

mg/kg/day (day 

6 to 15 of 

gestation)

No treatment related effects on external 

abnormalities, soft tissues abnormalities and 

skeletal abnormalities. No increases in fetal 

malformations were noted that varied from the 

control group.

NOAEL maternal 140 mg/kg/day

OECD SIDS 2004

HSDB 2006

Goldenthal et al, 

1979b; Short et al., 

1986

1-hr Inhalation 

Neurotoxicity study –

rats

Maleic acid

0.72 mg/L Neurotox – produced generalized inactivity, 

hyperpnea and sedation within 15 mins. No 

significant findings in gross necropsy.

HSDB 2006

Bacterial gene 

mutation test

Maleic anhydride and 

maleic acid

Up to 600 

umol/plate

Negative with and without metabolic 

activation

OECD SIDS 2004

HSDB 2006

In vivo mammalian 

(rat) bone marrow 

chromosomal 

aberration test

Maleic anhydride

N/A Negative OECD SIDS 2004
18

Table 3. Toxicology Profile of maleic acid and anhydride

Guideline No./ 

Study Type

Doses Levels Results MRID No. 

(year)/References

In vitro chromosomal 

test

Maleic anhydride

N/A Positive with and without metabolic 

activation. Unclear if this was due to maleic 

anhydride or to acidic environment due to 

hydrolysis to acid.

OECD SIDS 2004

90 day metabolism 

study – dog

Maleic anhydride

60 mg/kg/day Uptake rate 3.49 x 10-3 per day

Elimination rate 8.32 x 10-2 per day

99% Steady state was reach by day 55 of 

study.

HSDB 2006

B. Toxicity Endpoint Selection

The 2-year oral toxicity study in rats was selected for dietary and dermal exposure 

scenarios (all durations) for this risk assessment. The NOAEL in this study was 10

mg/kg/day. The LOAEL was 32 mg/kg/day based on slight to marginal decreases in 

bodyweight. The rationale for selecting this study for the dietary is based on the fact that 

this study provided the lowest and most conservative toxicity endpoint in the most 

sensitive species for oral after a long term exposure. No dermal toxicity studies are 

available for maleic anhydride; the dermal risk assessment was conducted using the most 

sensitive conservative oral endpoint. In addition, this NOAEL would be protective of 

kidney and bladder effects seen at the LOAEL of 20 mg/kg/day in the reproduction study 

since these organs were examined in the 2-year toxicity study in rats. Uncertainty Factor 

of 100x was applied, 10x for interspecies variability and 10x for intraspecies variability. 

A value of 33% absorption will be used for dermal exposure scenarios based on an 

estimation of the ratios between an oral and dermal LD50 for the rabbits.

The 6-month inhalation toxicity study in rats was selected for inhalation exposure 

scenarios (all durations) for this risk assessment. The NOAEL in this study was 3.3 

mg/m3or 0.93 mg/kg/day based on localized eye/nasal irritation effects seen at the 

LOAEL of 9.8 mg/m3. Since the major effect of maleic anhydride is irritation via 

inhalation, this endpoint is protective of any systemic toxicity seen at concentrations of 

32 mg/m3and above seen in the 28-day inhalation toxicity study. An uncertainty factor of 

100x was applied, 10x for interspecies variability and 10x for intraspecies variability.

Table 4. Summary of Toxicological Doses and Endpoints of Maleic Anhydride and Maleic Acid for Use in 

Human Health Risk Assessment

Exposure/Scenario Point of Departure and 

Uncertainty/Safety 

Factors

RfD, PAD, 

LOC for Risk 

Assessment

Study and Toxicological Effects

Acute dietary 

(General population

including infants and 

children)

An acute effect was not found in the database therefore an acute dietary assessment is 

not necessary.

Chronic dietary 

(All populations)

NOAEL= 10 mg/kg/day 

UFA = 10 x

UFH = 10 x

Chronic RfD = 

10 mg/kg/day

[2-year oral toxicity-rat] LOAEL = 

32 mg/kg/day based on slight to 

marginal decreases in bodyweight.
19

Table 4. Summary of Toxicological Doses and Endpoints of Maleic Anhydride and Maleic Acid for Use in 

Human Health Risk Assessment

Exposure/Scenario Point of Departure and 

Uncertainty/Safety 

Factors

RfD, PAD, 

LOC for Risk 

Assessment

Study and Toxicological Effects

FQPA SF = 1 x cPAD = 0.1

mg/kg/day

Incidental oral shortterm 

(1 to 30 days)

NOAEL= 10 mg/kg/day 

UFA = 10 x

UFH = 10 x

FQPA SF = 1 x

LOC for MOE 

= 100

[2-year oral toxicity-rat] LOAEL = 

32 mg/kg/day based on slight to 

marginal decreases in bodyweight.

Incidental oral 

intermediate-term 

(1 to 6 months)

NOAEL= 10 mg/kg/day 

UFA = 10 x

UFH = 10 x

FQPA SF = 1 x

LOC for MOE 

= 100

[2-year oral toxicity-rat] LOAEL = 

32 mg/kg/day based on slight to 

marginal decreases in bodyweight.

Dermal short- and 

intermediate term 

Oral study NOAEL= 10

mg/kg/day (dermal

absorption rate = 33%)

UFA = 10 x

UFH = 10 x

FQPA SF = 1 x

LOC for MOE 

= 100

[2-year oral toxicity-rat] LOAEL = 

32 mg/kg/day based on slight to 

marginal decreases in bodyweight.

Inhalation short- and 

intermediate term 

NOAEL= 0.93 mg/kg/day 

(inhalation absorption rate 

= 100%)

UFA = 10 x

UFH = 10 x

FQPA SF = 1 x

LOC for MOE 

= 100 

[6-month inhalation toxicity-rat] 

LOAEL = 1000 mg/kg/day based on 

reduction in body weights and 

hyperplastic and metaplastic changes 

of nasal tissues (considered 

reversible).

Cancer (Oral, dermal, 

inhalation)

Based on two 2-year chronic dietary studies on maleic anhydride, no increases in 

tumor incidence that were considered related to maleic anhydride exposure up to 750 

mg/kg/day were identified, there is a low concern for maleic anhydride as a potential 

carcinogen.

UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members 

of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. UFS = use of a short-term 

study for long-term risk assessment. UFDB = to account for the absence of data or other data deficiency. FQPA SF = 

Food Quality Protection Act Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = 

reference dose. MOE = margin of exposure. LOC = level of concern.

C. Special Considerations for Infants and Children

FFDCA, as amended by FQPA, directs the Agency to use an additional 10X safety factor 

(SF), to account for potential pre- and postnatal toxicity and completeness of the data 

with respect to exposure and toxicity to infants and children. FQPA authorizes the 

Agency to modify the 10X FQPA SF only if reliable data demonstrate that the resulting 

level of exposure would be safe for infants and children. EPA concludes that the FQPA 

safety factor could be reduced to 1X for maleic anhydride for the following reasons:

i. The toxicity database for maleic anhydride contains the following acceptable 

studies: subchronic and chronic dietary, subchronic inhalation, 2-gen reproductive study, 

12-week tetratogenic, neurotox and genotox studies. The database is considered as 

adequate for FQPA assessment.
20

ii. There is no evidence of increased susceptibility of infants and children due to preand post-natal exposure to maleic anhydride. The NOAEL for offspring toxicity was 55 

mg/kg/day while parental toxicity was observed at the LOAEL of 20 mg/kg/day No 

developmental or parental systemic toxicity was observed at the highest dose tested (140 

mg/kg/day) in the developmental toxicity study in rabbits. 

iii. There is no indication that maleic anhydride is neurotoxic chemicals. A 1-hour 

inhalation exposure of rats to 0.72 mg/L of maleic acid produced generalized inactivity, 

hyperpnea and sedation within 15 minutes of exposure. Gross necropsy revealed no 

significant findings. Therefore, there is no need for additional UFs to account for 

neurotoxicity. 

iv. There is no indication that maleic anhdyride is an immunotoxic chemical. No 

immunotoxicity studies were available in the database maleic anhydride. However no 

immunotoxic effects were seen in the available studies, therefore there is no need for

additional UFs to account for immunotoxicity.

v. The dietary food exposure assessment utilizes proposed tolerance level or higher 

residues and 100% crop treated information for all commodities. By using these

screening-level assessments, chronic exposures/risks will not be underestimated.

Taking into consideration the available information, EPA concludes the additional 10X 

FQPA safety factor can be reduced to 1X.

IV. EXPOSURE ASSESSMENT

The petitioner requested the ability to use maleic anhydride and maleic acid in any type 

of pesticide i.e., insecticide, fungicide or herbicide on any application site i.e., 

agricultural crops, livestock, residential uses indoor and outdoor. The petitioner did not 

provide any exposure or risk assessments regarding human occupational or residential 

exposure. Resources constraints prohibit the Agency from conducting monographic, “allinclusive” assessments of exposure for all possible or imaginable combinations of 

methods of application to all possible application sites.

Therefore, the Agency has conducted a “screening-level” assessment of a wide variety of 

sites and use patterns in an effort to obtain a qualitative idea of the possible results of 

human exposures that might result from such combinations of methods of application and 

sites of application. 

It should be noted again, as indicated from the earlier discussion of toxicological 

properties, that the data and information regarding toxicological effects are limited. Thus 

the “screening-level” assessment is based upon some conservative assumptions. 
21

A. Dietary Exposure:

 i. Acute exposure. No adverse effects attributable to a single exposure of maleic 

anhydride or maleic acid were seen in the toxicity databases. Therefore, acute dietary 

risk assessment for maleic anhydride and maelic acid is not required.

 ii. Chronic exposure. The chronic dietary exposure assessment for this inert ingredient 

utilizes the Dietary Exposure Evaluation Model Food Commodity Intake Database 

(DEEM-FCID), Version 3.16, EPA, which includes food consumption information from 

the U.S. Department of Agriculture’s national health and Nutrition Examination Survey, 

“What We Eat In America”, (NHANES/WWEIA). This dietary survey was conducted 

from 2003 to 2008. In the absence of actual residue data, the inert ingredient evaluation is 

based on a highly conservative model which assumes that the residue level of the inert 

ingredient would be no higher than the highest established tolerance for an active 

ingredient on a given commodity. As to residue levels in food, no residue data were 

submitted for maleic anhydride and maleic acid. In the absence of specific residue data, 

EPA has developed an approach which uses surrogate information to derive upper bound 

exposure estimates for the subject inert ingredient. Upper bound exposure estimates are 

based on the highest tolerance for a given commodity from a list of high-use insecticides, 

herbicides, and fungicides. A complete description of the general approach taken to 

assess inert ingredient risks in the absence of residue data is contained in the 

memorandum entitled “Alkyl Amines Polyalkoxylates (Cluster 4): Acute and Chronic 

Aggregate (Food and Drinking Water) Dietary Exposure and Risk Assessments for the 

Inerts.” (D361707, S. Piper, 2/25/09) and can be found at http://www.regulations.gov in 

docket ID number EPA-HQ-OPP-2008-0738. In the case of maleic anhydride, an 

adjustment to the dietary exposure analysis was made to account for the use limitations of 

maleic anhydride (use as an inert ingredient in pesticide formulations applied to apples 

with a minimum preharvest interval of 21 days and use at a maximum concentration of 

3.5% in all other preharvest uses. The theoretical maximum residue values for apples and 

apple commodities resulting from the proposed use was revised from 25 ppm (which is 

based on highest active ingredient tolerance (captan)) to 4 ppm. The current tolerances 

(as of 2012) for active ingredients on apples is provided in the appendix. Based on these 

tolerances for apples, the established tolerances for apples that exceed 4 ppm are for 

active ingredients that have either post-harvest use on apples or have uses with relatively 

short (7 days or less) PHIs. Therefore it is reasonable to assume, as a worst-case, that the 

use of a pesticide product with a 21-day PHI on apples would not result in inert 

ingredient residues in excess of 4 ppm. This value is further supported by actual 

monitoring data for pesticides on apples such as the USDA Pesticide Data Program 

Calendar Year 2014 Annual Summary 

(https://www.ams.usda.gov/sites/default/files/media/2014%20PDP%20Annual%20Summ

ary.pdf) in which no pesticide residue was detected on apples at concentrations in excess 

of 4.2 ppm.

In the dietary exposure assessment, the Agency assumed that the residue level of the inert 

ingredient would be no higher than the highest tolerance for a given commodity. Implicit 

in this assumption is that there would be similar rates of degradation (if any) between the 
22

active and inert ingredient and that the concentration of inert ingredient in the scenarios 

leading to these highest of tolerances would be no higher than the concentration of the 

active ingredient.

The Agency believes the assumptions used to estimate dietary exposures lead to an 

extremely conservative assessment of dietary risk due to a series of compounded 

conservatisms. First, assuming that the level of residue for an inert ingredient is equal to 

the level of residue for the active ingredient will overstate exposure. The concentration of 

active ingredients in agricultural products is generally at least 50 percent of the product 

and often can be much higher. Further, pesticide products rarely have a single inert 

ingredient; rather there is generally a combination of different inert ingredients used 

which additionally reduces the concentration of any single inert ingredient in the 

pesticide product in relation to that of the active ingredient.

Second, the conservatism of this methodology is compounded by EPA’s decision to 

assume that, for each commodity, the active ingredient which will serve as a guide to the 

potential level of inert ingredient residues is the active ingredient with the highest 

tolerance level. This assumption overstates residue values because it would be highly 

unlikely, given the high number of inert ingredients, that a single inert ingredient or class 

of ingredients would be present at the level of the active ingredient in the highest 

tolerance for every commodity. Finally, a third compounding conservatism is EPA’s 

assumption that all foods contain the inert ingredient at the highest tolerance level. In

other words, EPA assumed 100 percent of all foods are treated with the inert ingredient at 

the rate and manner necessary to produce the highest residue legally possible for an 

active ingredient. In summary, EPA chose a very conservative method for estimating 

what level of inert residue could be on food, and then use this methodology to choose the 

highest possible residue that could be found on food and assumed that all food contained 

this residue. No consideration was given to potential degradation between harvest and 

consumption even though monitoring data shows that tolerance level residues are 

typically one to two orders of magnitude higher than actual residues in food when 

distributed in commerce. 

Accordingly, although sufficient information to quantify actual residue levels in food is 

not available, the compounding of these conservative assumptions will lead to a 

significant exaggeration of actual exposures. EPA does not believe that this approach 

underestimates exposure in the absence of residue data.

Table 5. Summary of Chronic Dietary Exposure and Risk of Maleic Anhydride and Maleic Acid

Population Subgroup cPAD (mg/kg/day) Chronic

Exposure (mg/kg/day) %cPAD

General U.S. Population

0.10

0.015922 15.9%

All Infants (<1 year old) 0.040859 40.9%

Children 1-2 years old 0.072389 72.4%

Children 3-5 years old 0.046364 46.4%

Children 6-12 years old 0.022157 22.2%

Youth 13-19 years old 0.011039 11.0%

Adults 20-49 years old 0.011143 11.1%

Adults 50+ years old 0.011602 11.6%
23

Females 13-49 years old 0.011376 11.4%

Based on analyses of estimated dietary risks for the general U.S. population and various 

population subgroups, the chronic dietary exposure estimates for maleic anhydride and 

maleic acid are significantly below the Agency’s level of concern for all supported 

commodities. The chronic dietary exposure estimate for the highest exposed population 

subgroup, children 1-2 years old is 72.4 % of the chronic population adjusted dose 

(cPAD). The chronic dietary exposure estimate for the general U.S. population is 15.9% 

of the cPAD.

iii. Cancer exposure. Maleic anhydride and maleic acid are not expected to be 

carcinogenic based on Oncologic modeling. Also the genotoxicity studies on maleic 

anhydride were negative. Therefore, a cancer dietary exposure assessment is not 

necessary to assess cancer risk.

B. Residential (Non-Occupational) Exposure:

The screening-level assessment was conducted using an Antimicrobials Division (AD) 

assessment tool developed to assess Amine Oxide (“900439, (C10-16); C10-C18-

Alkyldimethylamine oxides; Human Health Risk Assessment and Ecological Effects 

Assessment to Support Proposed Exemption from the Requirement of a Tolerance When 

Used as Inert Ingredients in Pesticide Formulations.” 22 SEPT 2009; Memorandum L. 

Austin to P. Shah; Reg. Div./OPP/EPA). The assessment tool uses standard assessment 

methodology developed by the Antimicrobials Division and the Science Advisory 

Council for Exposure (EXPOSAC), Health Effects Division/Office of Pesticide 

Programs. The methodology can also be found in part at: 

http://www.epa.gov/pesticides/science/residential-exposure-sop.html

http://www.epa.gov/pesticides/science/post-app-exposure-data.html

http://www.epa.gov/pesticides/science/handler-exposure-data.html.

In its simplest form, exposure is assessed as follows:

Unit Exposure * Amount applied/Unit * Units treated/day * absorption factor ÷ Body Wt.

(mg/lb handled) (lb applied/unit) (acres etc) kg

Inhalation and oral absorption are assumed to be 100%. Dermal absorption is estimated to 

be 33%. The maximum concentration of maleic anhydride and maleic acid in a pesticide 

formulations is no more than 3.5%.

The result is an estimated average daily dose (ADD or “exposure”) expressed as mg 

material/kg/day. That value is used then to calculate the Margin of Exposure (MOE) 

(estimated measure of risk). An MOE is calculated by dividing the value of the average 

daily dose into the toxicological endpoint of concern (also expressed in mg 

material/kg/day). Typically, resulting MOEs ≥ 100 do not exceed the Agency’s level of 

concern. MOEs less than 100 typically exceed the Agency’s level of concern.
24

For the dietary and dermal exposure assessments the Agency uses the toxicological

endpoint of 10 mg/kg/day identified from the 2-year oral toxicity study in rats based on 

slight to marginal decreases in bodyweight. For inhalation exposure assessment the 

Agency uses the toxicological endpoint of 0.93 mg/kg/day identified from the 6-month 

inhalation toxicity study in rats based on reduction in body weights and hyperplastic and 

metaplastic changes of nasal tissues (considered reversible).

Results of the screening-level assessments are presented in the document. Margins of 

exposure are presented as summaries for residential “handlers” (non-occupationally 

associated applicators) and for occupational pesticide handlers. Since lawn and turf uses 

may be involved, assessments of post-application exposures to “residents” were also 

conducted. Estimated exposure doses as well as margins of exposure are presented for 

inhalation, dermal and incidental oral exposure. Post-application oral exposures (hand-tomouth activity) are presented for toddlers (children ages 1-2 years), the highest exposed 

population. 

i. From non-dietary exposure. The term “residential exposure” is used in this document 

to refer to non-occupational, non-dietary exposure (e.g., for lawn and garden pest control, 

indoor pest control, termiticides, and flea and tick control on pets). Maleic anhydride and 

maleic acid may be used as inert ingredients in pesticide products that are registered for 

specific uses that may result in indoor or outdoor residential exposures. Possible routes of 

exposure are expected to be inhalation and dermal exposure as a result of contact with 

areas treated with maleic anhydride and maleic acid. A screening level residential 

exposure and risk assessment was completed. The Agency conducted exposure 

assessments based on typical end-use product application methods and labeled 

application rates. However no example product labels were provided by the registrant and 

conservative assumptions for application rates were used. The Agency conducted an 

assessment to represent worse-case residential exposure by assessing residential 

applicator and post-application exposures and risk from maleic anhydride and maleic acid

in pesticide formulations.

Table 6. Residential Handler Short- and Intermediate-term Exposures and Risks for Maleic Anhydride 

and Maleic Acid

Pesticid

e Type

Exposure 

Scenario

Applicati

on Rate1

Exposed 

Populatio

n & 

Exposure 

Duration2

Dermal 

Dose 

(mg/kg/da

y)3

Inhalation 

Dose 

(mg/kg/da

y)3

Derm

al

MOE4

Inhalati

on 

MOE4

Total

Combin

ed

MOE5

Herbicid

e/

Fungicid

e/

Insectici

de

Liquids/Low 

Pressure 

Handwand

0.0315

lb/gal

Short & 

Intermedi

ate Term

0.024688 0.0000059 410 160,000 400

Liquids/Hos

e End 

Sprayer

Short & 

Intermedi

ate Term

0.007147 0.0000335 1400 28,000 1300

Liquids/Trig

ger SprayerHG, IS, 

C&C

Short & 

Intermedi

ate Term

0.035083 0.0000037 290 250,000 280
25

Indoor 

Surface 

Cleaner

Mopping 0.0046 

lb/gal

Short & 

Intermedi

ate Term

0.001347 0.0001357 7400 6900 3600

Wiping 0.0379 

lb/gal

Short & 

Intermedi

ate Term

0.058402 0.0041500 170 220 97

Aerosol 

Spray

0.0274 

lb/gal

Short & 

Intermedi

ate Term

0.002341 0.0000774 4300 12000 3200

1 Application rates for maleic anhydride and maleic acid are based on default values provided in the AD assessment tool. Inert 

ingredient limited to 3.5% of formulation.

2 ST and IT indicate short- or intermediate-term exposure durations

3 Average Daily Dose = Application rate * Quantity Treated (5 gallons) * Unit Exposure (Varies by exposure scenario) * 

Absorption Factor (33%) / Body Weight (80 kg)

4 MOE = PoD (NOAEL of 10 mg/kg/day for dermal and 0.93 for inhalation)/ Daily dose (mg/kg/day)

5 Total MOE = 1/((1/ Dermal MOE)+(1/inhalation MOE))

EPA has calculated the outdoor residential applicator exposures. Three exposure 

scenarios, low pressure handwand, hose end sprayer and trigger sprayer were assessed for 

each pesticide type, herbicide, insecticide and fungicide in both short- and intermediateterm scenarios. The combined outdoor residential applicator dermal and inhalation 

MOEs ranged from 280 to 1300. As the level of concern is for MOEs that are lower than 

100, these MOEs are not of concern. 

EPA has calculated the indoor residential applicator exposures. Three exposure scenarios, 

mopping, wiping and aerosol spray were assessed in both short- and intermediate-term 

scenarios. The combined indoor residential applicator dermal and inhalation MOEs 

ranged from 97 to 3600. The level of concern is for MOEs that are lower than 100. The 

MOE of 97 for indoor surface cleaner wiping is lower than the level of concern and is the 

only MOE to be below 100. However with all the conservatisms incorporated into the 

calculation, this scenario is not expected to be of particular concern.

Table 7. Residential Post-Application Short- and Intermediate-term Exposures and Risks for Maleic 

Anhydride and Maleic Acid

Pesticide 

Type

Exposure Scenario Application 

Rate1

Exposed Population & 

Exposure Duration2

Daily Dose 

(mg/kg/day)3

MOE4

Outdoor Products

Herbicide

Insecticide

Fungicide

Post-App Dermal 

Treated Lawn

0.158 lb/day

Adult ST 0.0105639 950

Adult IT 0.0053184 1900

Child ST 0.020205 490

Child IT 0.0101025 990

Hand-to-Mouth from 

Treated Lawn

Child ST 0.0023549 4200

Child IT 0.0011186 8900

Object-to-Mouth 

from Treated Lawn

Child ST

0.0005887 17000

Child IT

1 Application rates for maleic anhydride and maleic acid are based on default values provided in the AD assessment tool. Inert 

ingredient limited to 3.5% of formulation.

2 ST and IT indicate short- or intermediate-term exposure durations

3 Daily Dose is calculated differently for each exposure scenario. Refer to AD assessment tool for more details.

4 MOE = PoD (NOAEL of 10 mg/kg/day for dermal and 0.93 for inhalation)/ Daily dose (mg/kg/day)
26

The short- and intermediate-term MOEs for residential post-application dermal exposure 

to treated lawns was calculated to be 950 and 1900 for adults respectively and 490 and 

990 for children respectively. The post-application child (hand-to-mouth) short-term 

MOE was calculated to be 4200 from treated lawns. As the level of concern is for MOEs 

that are lower than 100, these MOEs are not of concern.

V. AGGREGATE RISK ASSESSMENT

EPA determines whether acute and chronic pesticide exposures are safe by comparing 

aggregate exposure estimates to the acute population adjusted dose (aPAD) and chronic 

population adjusted dose (cPAD). The aPAD and cPAD represent the highest safe 

exposures, taking into account all appropriate safety factors (SFs). EPA calculates the 

aPAD and cPAD by dividing the POD (i.e. toxicological endpoint) by all applicable UFs. 

For linear cancer risks, EPA calculates the probability of additional cancer cases given 

the estimated aggregate exposure. Short-, intermediate-, and chronic-term risks are 

evaluated by comparing the estimated aggregate food, water, and residential exposure to 

the POD to ensure that the MOE called for by the product of all applicable UFs is not 

exceeded. 

i. Acute Dietary Risk. 

An acute aggregate risk assessment takes into account exposure estimates from acute 

dietary consumption of food and drinking water using the exposure assumptions 

discussed in Section IV for acute exposure. However there was no hazard attributable to 

a single exposure seen in the toxicity database for maleic anhydride and maleic acid; 

therefore there is no concern for an acute dietary risk and an acute aggregate risk 

assessment was not conducted.

ii. Chronic Dietary Risk. 

A chronic aggregate risk assessment takes into account exposure estimates from chronic 

dietary consumption of food and drinking water using the exposure assumptions 

discussed in Section IV from chronic exposure. The chronic analysis was based on a 2-

year oral toxicity study with a NOAEL of 10 mg/kg/day based on slight to marginal 

decreases in bodyweight. A chronic dietary risk assessment at the initially-proposed use 

limitation of 5% by weight in the pesticide formulation resulted in potential chronic 

dietary risk of concern. The petitioner subsequently agreed to a use limitation of 3.5% in 

the pesticide formulation. The chronic dietary exposure from food and water to maleic 

anhydride and maleic acid as an inert ingredient at a concentration not to exceed 3.5% by 

weight in pesticides applied to growing crops is 13.3% of the cPAD for the U.S. 

population and 49.4% for children 1-2 yrs old, the most highly exposed population 

subgroup.
27

iii. Aggregate Cancer Risk for U.S. Population. 

The Agency has not identified any concerns for carcinogenicity relating to maleic 

anhydride and maleic acid; therefore, a cancer dietary exposure assessment was not 

performed and an aggregate risk assessment is not a concern.

iv. Short-term Aggregate Risk. 

Short-term aggregate exposure takes into account short-term residential exposure plus 

chronic exposure to food and water (considered to be a background exposure level). 

Maleic anhydride and maleic acid may be used as an inert ingredient in pesticide products 

that could result in short-term residential exposure. The Agency has determined that it is 

appropriate to aggregate chronic exposure through food and water with short-term 

residential exposures. Using the exposure assumptions described in Section IV, EPA has 

calculated the combined short-term aggregated food, water, and residential exposures. 

The adult short-term aggregate MOE was calculated to be 112 for both males and 

females. Adult aggregate MOE combines average food and water exposure from the 

chronic dietary exposure with high end residential applicator exposure (liquid trigger

sprayer). As the level of concern is for MOEs that are lower than 100, this MOE is not of 

concern. EPA has concluded the combined short-term aggregated food, water, and 

residential exposures results in an aggregate MOE of 105 for children. Children’s 

aggregate MOE combines average food and water exposure from the chronic dietary 

exposure with residential exposure associated with contact with treated lawns (post-app 

dermal exposure + hand-to-mouth + object-to-mouth). As the level of concern is for 

MOEs that are lower than 100, these MOEs are not of concern.

Table 8. Short-Term Aggregate Risk Calculations for Maleic Anhydride and Maleic Acid

Population

PoD

mg/kg/day LOC1

Max 

Allowable

Exposure2

mg/kg/day

Average

Food & 

Water

Exposure3

mg/kg/day

Residential 

Exposure4

mg/kg/day

Aggregate 

MOE

(food and

residential)5

Adult 10 100 0.10 0.015922 0.07312 112

Child 10 100 0.10 0.072389 0.02315 105

1 The LOC (Level of Concern) is based on the standard inter-, intra-species uncertainty factors totaling 100.

2 Maximum Allowable Exposure (mg/kg/day) = PoD (Point of Departure)/LOC.

3 Average Food & Water Exposure = Chronic Dietary Exposure Table 5.

4 Residential Exposure = Adult worse case scenarios for [Handler Exposure + Post App. Exposure]; Child [Post App Dermal + 

HTM +OTM]

5 Aggregate MOE = [PoD/ (Avg Food & Water Exposure + Residential Exposure)].

v. Intermediate-Term Aggregate Risk. 

Intermediate -term aggregate exposure takes into account intermediate-term residential 

exposure plus chronic exposure to food and water (considered to be a background 

exposure level). Maleic anhydride and maleic acid may be used as an inert ingredient in 

pesticide products that could result in intermediate-term residential exposure. The 

Agency has determined that it is appropriate to aggregate chronic exposure through food 

and water with intermediate-term residential exposures. Using the exposure assumptions 
28

described in Section IV, EPA has calculated the combined intermediate-term aggregated 

food, water, and residential exposures. The adult intermediate-term aggregate MOE was 

calculated to be 178 for both males and females. Adult aggregate MOE combines average 

food and water exposure from the chronic dietary exposure with high end residential 

applicator exposure (liquid trigger sprayer). As the level of concern is for MOEs that are 

lower than 100, this MOE is not of concern. EPA has concluded the combined 

intermediate-term aggregated food, water, and residential exposures results in an 

aggregate MOE of 119 for children. Children’s aggregate MOE combines average food 

and water exposure from the chronic dietary exposure with residential exposure 

associated with contact with treated lawns (post-app dermal exposure + hand-to-mouth + 

object-to-mouth). As the level of concern is for MOEs that are lower than 100, these 

MOEs are not of concern.

Table 9. Intermediate-Term Aggregate Risk Calculations for Maleic Anhydride and Maleic Acid

Population

PoD

mg/kg/day LOC1

Max 

Allowable

Exposure2

mg/kg/day

Average

Food & 

Water

Exposure3

mg/kg/day

Residential 

Exposure4

mg/kg/day

Aggregate 

MOE

(food and

residential)5

Adult 10 100 0.10 0.015922 0.04041 178

Child 10 100 0.10 0.072389 0.01181 119

1 The LOC (Level of Concern) is based on the standard inter-, intra-species uncertainty factors totaling 100.

2 Maximum Allowable Exposure (mg/kg/day) = PoD (Point of Departure)/LOC.

3 Average Food & Water Exposure = Chronic Dietary Exposure Table 5.

4 Residential Exposure = Adult worse case scenarios for [Handler Exposure + Post App. Exposure]; Child [Post App Dermal + 

HTM +OTM]

5 Aggregate MOE = [PoD/ (Avg Food & Water Exposure + Residential Exposure)].

VI. OCCUPATIONAL EXPOSURE/RISK PATHWAY

The representative occupational scenarios selected by the Agency for assessment are 

evaluated based on likely maximum application rates for products which may contain the inert 

ingredient for the short-term exposure assessment, and average application rates for products 

likely to contain the inert ingredient for the intermediate- and long-term exposure durations. 

Active ingredient application rates are corrected for the maximum amount of inert ingredient 

likely to be in the final formulations to determine exposure and risk from exposure to the inert 

ingredient by fungicide/insecticide or herbicide. 

The Agency traditionally considers a level of concern (LOC) for these risk assessments to 

be an MOE of 100 based on the standard 10X inter and 10X intra species extrapolation safety 

factors. 

A. Occupational Handler Risk

Exposure Scenarios

Dermal and inhalation exposure are estimated using the Pesticide Handlers Exposure 
29

Database (PHED) and Outdoor Residential Exposure Task Force (ORETF) data. The 

analytical techniques are those developed by the Science Policy Council on Exposure 

(ExpoSAC), Heath Effects Division, Office of Pesticide Programs, US Environmental 

Protection Agency. The quantitative exposure/risk assessment developed for occupational 

handlers to support the requested exemption for the inert ingredient based on scenarios to 

represent the highest potential exposure. 

The algorithm used to estimate exposure is:

U.E. * AR * Units Treated/day * absorption factor ÷ body weight.

UE Unit Exposure in mg of material per lb of material handled. Unit 

Exposures are derived in the Pesticide Handlers Exposure Database 

(PHED) and are recently summarized in the “Occupation Pesticide 

Handler Unit Exposure Surrogate Reference Table” US EPA Office of 

Pesticide Programs, March 2012 (unpublished)

AR Application Rate in lbs of material per unit (acres). In this case taken from 

Herbicide Occupational Handler Inert Exposure Calculator. A limitation 

of 3.5% in formulation was applied to these application rate. 

Units Treated/day - - In this case acres treated per day taken from the Antimicrobials 

Division (AD) assessment tool developed to assess Amine Oxide 

(“900439, (C10-16); C10-C18-Alkyldimethylamine oxides; Human Health 

Risk Assessment and Ecological Effects Assessment to Support Proposed 

Exemption from the Requirement of a Tolerance When Used as Inert 

Ingredients in Pesticide Formulations.” 22 SEPT 2009

AF Absorption factor - - 100% default for inhalation routes of exposure and 

an estimated 33% for dermal route of exposure

BW Body Weight - - 80 kg for combined adults in the U.S. Taken from “Use 

of New Human Body Weight Data as Presented in the EPA’s Exposure 

Factors Handbook: 2011 Edition” HED “HotSheet” No. 31.

In this case occupational exposures are presented for aerial applicators, ground 

applicators and for mixer/loaders preparing and applying liquid formulations diluted for 

use in applications. These are the occupational activities believed to be associated with 

the highest exposures use patterns. The occupation exposure assessment utilized the 

baseline values for highest exposure herbicide, insecticide and fungicide. Only the 

herbicide data is provided below because it provided the lowest and most conservative 

MOEs. 

Table 10. Summary of Exposure & Risk to Occupational Handlers From Maleic Anhydride and Maleic 

Acid

Scenario Unit 

Exposure1

Application 

Rate1

lb inert/unit

Units 

Treated1

Avg. Daily

Exposure2

MOE3
30

1. Default values are taken from Antimicrobials Division (AD) assessment tool developed to assess Amine Oxide (“900439, (C10-

16); C10-C18-Alkyldimethylamine oxides

2. Average Daily Exposure = Unit Exposure * Application Rate (corrected for 5% limitation) * Units Treated * Absorption Rate÷ 

80 kg Body Weight

3. MOE = Margin of Exposure = NOAEL  ADE. 

mg inert/lb 

handled

mg inert/kg 

bw/day

Insecticide Mixer/Loaders

Liquids: Aerial Dermal:

Single-layer 

gloves

0.023

Inhalation: 

No respirator 

0.0012

0.07 lb ai/A

Corn (Max/ST) 1200 A/day

Dermal:

Single-layer gloves

0.00797

Inhalation: 

No respirator 

0.00126

Dermal:

1300

Inhalation:

740

Combined:

460

Liquids: Airblast Dermal:

Single-layer 

gloves

0.023

Inhalation: 

No respirator 

0.0012

0.315 lb ai/A

Nut Trees 

(Max/ST)

40 A/day

Dermal:

Single-layer gloves

0.00120

Inhalation: 

No respirator 

0.00019

Dermal:

8400

Inhalation:

4900

Combined:

3100

Liquids: 

Groundboom

Dermal:

Single-layer 

gloves

0.023

Inhalation: 

No respirator 

0.0012

0.07 lb ai/A

Corn (Max/ST) 200 A/day

Dermal:

Single-layer gloves

0.00133

Inhalation: 

No respirator

0.00021

Dermal:

7500

Inhalation:

4400

Combined:

2800

Insecticide Applicator

Liquid: Airblast Dermal:

Single-layer 

gloves

0.24

Inhalation:

Open Cab

0.0045

0.315 lb ai/A

Nut Trees 

(Max/ST)

40 A/day

Dermal:

Single-layer gloves

0.01247

Inhalation:

Open Cab

0.00071

Dermal:

800

Inhalation:

1300

Combined:

500

Liquid: Groundboom Dermal:

Single-layer 

gloves

0.014

Inhalation:

Open Cab

0.00074

0.07 lb ai/A

Corn (Max/ST) 200 A/day

Dermal:

Single-layer gloves

0.00081

Inhalation:

Open Cab

0.00013

Dermal:

12000

Inhalation:

7200

Combined:

4500

Insecticide Mixer/Loader/Applicator

Liquid: Low 

Pressure handwand

Dermal:

Single-layer 

gloves

0.43

Inhalation:

No respirator

0.030

0.252 lb ai/A

Ornamentals 

(Max/ST)

5 A/day

Dermal:

Single-layer gloves

0.00223

Inhalation:

No respirator

0.00047

Dermal:

4500

Inhalation:

2000

Combined:

1400
31

The inhalation absorption was default at 100% and the dermal absorption was estimated 

to be 33%. The dermal toxicity was also assumed to be equivalent to oral toxicity

(NOAEL 10 mg/kg/day). Risks were calculated using the MOE approach, which is a ratio 

of the exposure to the toxicological PoD. Occupational handler risks are not of concern. 

The Agency’s level of concern for inhalation and dermal exposure is for MOEs <100. 

The combined occupational handler combined dermal and inhalation MOEs ranged from 

460 to 4500. As the level of concern is for MOEs that are lower than 100, these MOEs 

are not of concern.

B. Occupational Post-Application Risk

Exposure Scenarios

RD uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred 

to as re-entry exposure). Such exposures may occur when workers enter previously 

treated areas to perform job functions, including activities related to crop production, 

such as scouting for pests or harvesting. Post-application exposure levels vary over time 

and depend on such things as the type of activity, the nature of the crop or target that was 

treated, the type of pesticide application, and the chemical’s degradation properties. In 

addition, the timing of pesticide applications, relative to harvest activities, can greatly 

reduce the potential for post-application exposure. Inhalation exposures are also not 

typically calculated for occupational post-application scenarios because inhalation 

exposures generally account for a negligible percentage of the overall body burden for 

most pesticide chemicals.

Post-application worker exposure is estimated using HED procedure that assumes 20% of 

the application rate is available as dislodgeable foliar residue on the day of treatment. 

HED does not expect post application exposure to exceed short term exposure. Therefore, 

only short term exposure are assessed.

HED expects post-application agricultural exposures to workers would typically be shortterm (1-30 days). The following convention is used to estimate post-application 

agricultural worker exposure. 

DFRt = AR * F * (1-D)t* CF2 * CF3 where:

DFR = Dislodgeable Foliar Residue

AR = Application rate (lb inert/A)

F = fraction of inert retained on foliage (unitless) (default 20%)

D = fraction of residue that dissipates daily (unitless) (default 10%)

T = post application day on which exposure is being assessed

CF2 = weight unit conversion factor to convert the lbs inert in the application rate to μg 

for the DFR value (4.54E8 μg/lb)

CF3 = Area unit conversion factor to convert the surface area units (ft2) in the application 

rate to cm2for the DFR value (1.08E-3 ft2/cm2or 2.47E-8 acre/cm2)
32

Average Daily Dose (ADD) (mg inert/kg/day) = DFR μg/cm2 * TC cm2/hr * hr/day * 

0.001 mg/μg * 1/70 kg

In this case occupational post-application exposures are presented for tall field row, turf 

and for vinetrellis. These are the post-occupational activities believed to be associated 

with the highest exposures use patterns. The occupation post-application exposure 

assessment utilized the baseline values for highest exposure herbicide, insecticide and 

fungicide. The default value is provided below because it provided the lowest and most 

conservative MOEs. 

1. Default values are taken from Occupational Postapplication Risk Assessment Calculator Version 2 (12/2008)

2. Dislodgeable foliar residue = Fraction of inert retained on foliage * Application Rate (corrected for 3.5% limitation) * (1-daily 

dissipation)t * conversion factors 

3. Short-term dose = DFR * Tc * hours of daily exposure (8 hrs) * conversion factors (μg to mg) / 80 kg

4. MOE = Margin of Exposure = NOAEL  Short-term dose. 

The dermal absorption was estimated to be 33%. The dermal toxicity was also assumed 

to be equivalent to oral toxicity (NOAEL 10 mg/kg/day). Risks were calculated using the 

MOE approach, which is a ratio of the exposure to the toxicological PoD. Occupational 

post-application risks are not of concern. The Agency’s level of concern for dermal 

exposure is for MOEs <100. The post application occupational handler MOEs ranged 

from 110 to 390 for the high exposure potential scenarios. As the level of concern is for 

MOEs that are lower than 100, these MOEs are not of concern.

Table 11. Summary of Exposure & Risk to Occupational Post-Application From Maleic Anhydride and 

Maleic Acid

Exposure Potential Transfer 

Coefficients1

cm2/hr

Application 

Rate1

lb inert/Acre

DFR 

Levels2

μg/cm2

Shortterm Dose3

mg inert/kg 

/day

MOE4

Insecticide Short-term Tall Field Row

Low: scouting, weeding 

immature/low foliage plants 100

0.35 lb ienrt/A 0.132

0.0062 3900

Medium: scouting, weeding more 

mature/foliaged plants 400 0.0247 960

High: scouting, irrigation, weeding 

mature/full foliage plants 1000 0.0617 390

Insecticide Short-term Turf

Low: Mowing 500 0.35 lb inert/A 0.687 0.008 3100

High: Transplanting, handweeding 6800 0.105 230

Insecticide Short-term Vinetrellis

Low: Hedging, irrigation, scouting, 

hand weeding, training/tying 

blueberries

500

0.245 lb inert/A 1.347

0.0216 1100

Medium: Scouting, training, tying 1000 0.0432 550

High: hand harvest, leaf pulling, 

thinning, pruning, training/tying 

grapes

5000 0.2160 110
33

VII. CUMULATIVE EXPOSURE

Cumulative effects from substances with a common mechanism of toxicity. Section 

408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or 

revoke a tolerance, the Agency consider “available information” concerning the cumulative 

effects of a particular pesticide's residues and “other substances that have a common mechanism 

of toxicity.”

EPA has not found maleic anhydride and maleic acid to share a common mechanism of 

toxicity with any other substances, and that maleic anhydride and maleic acid do not appear to 

produce a toxic metabolite produced by other substances. For the purposes of this tolerance 

action, therefore, EPA has assumed that maleic anhydride and maleic acid do not have 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 EPA's website at 

http://www.epa.gov/pesticides/cumulative.

VIII. ENVIRONMENTAL JUSTICE STATEMENT 

Potential areas of environmental justice concerns, to the extent possible, were considered 

in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal 

Actions to Address Environmental Justice in Minority Populations and Low-Income 

Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, RD estimates risks 

to population subgroups from pesticide exposures that are based on patterns of that subgroup’s 

food and water consumption, and activities in and around the home that involve pesticide use in 

a residential setting. Extensive data on food consumption patterns are compiled by the USDA 

under CSFII and are used in pesticide risk assessments for all registered food uses of a pesticide. 

These data are analyzed and categorized by subgroups based on age, season of the year, ethnic 

group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, 

specialized subgroups and exposure assessments are performed when conditions or 

circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of 

pesticide products and associated risks for adult applicators and for toddlers, youths, and adults 

entering or playing on treated areas post-application are evaluated. Further considerations are 

currently in development as OPP has committed resources and expertise to the development of 

specialized software and models that consider exposure to bystanders and farm workers as well 

as lifestyle and traditional dietary patterns among specific subgroups.

IX. ENVIRONMENTAL FATE CONSIDERATIONS
34

Maleic anhydride has a melting point of 51.2 to 53.10°C, a boiling point of 1850°C, and 

vapor pressures of 15.1, 37.7, and 108 Pa at 22, 30, and 400°C, respectively. The log Kow of 

maleic anhydride (as maleic acid) is –2.61. The water solubility of maleic anhydride (as maleic 

acid) was ~400 g/L at 20°C. Maleic acid has a melting point of 130-1440°C, a boiling point of 

1380°C, and a vapor pressure of 4.8 x 10-3 Pa at 250°C.

Maleic anhydride and maleic acid are not persistent in the environment and are not 

expected to bioaccumulate in food webs. In the presence of water, maleic anhydride rapidly 

hydrolyzes to form maleic acid. The half-life of maleic anhydride in air is estimated to be 4.2 to 

16 hours; due primarily to direct reactions with photochemically generated hydroxyl radicals. 

For maleic acid, the half-life in air is estimated to be 1.346 and 1.205 days for the cis- and transisomers, respectively.

Maleic anhydride and maleic acid are readily biodegraded under aerobic conditions in 

sewage sludge, and are expected to biodegrade in soil and water as well. Fugacity-based fate and 

transport modelling suggest that maleic anhydride, hydrolyzed to maleic acid in water and under 

humid conditions, will partition primarily to water. Level I fugacity modelling indicates water as 

the primary compartment for distribution while Level III modelling indicates: air 0.0%, water 

50%, soil 50%, sediment 0.02%.

X. ECOTOXICITY

Because maleic anhydride rapidly hydrolyzes to form maleic acid in water, maleic acid 

and/or its salts are the actual form of the chemical evaluated in aquatic toxicity tests. The acute 

data regarding the acute toxicity of maleic anhydride and maleic acid in aquatic species are 

summarized below:

Fish Acute Toxicity

Acute toxicity to fish was tested for several species. Among the studies found reliable 

(Klimisch code 1B) were key studies on trout (Salmo gairdneri) and bluegill (Lepomis 

macrochirus) studies. These reported 96 hour LC50 of 75 mg/liter (ABC Laboratories 

1982a, 1982b). Test conditions were static and test material concentrations were not 

measured. Effects were observed only in the highest concentration (100 mg/liter); initial 

pH was 3.3 in that concentration, suggesting that toxicity was related to acidity. Dilution 

water was soft reconstituted water (total hardness of 40 to 45 mg/liter as CaCO3) with 

temperatures of 12oC (trout) and 22oC (bluegill).

Other published scientific studies (Klimisch code 2B or 2C) were a 96 hour LC50 of 230 

mg/liter for the mosquitofish (Gambusia affinis) (Wallen et al 1957), a 48 hour LC50 of 

115 mg/liter for Golden orfe (Leuciscus idus melanotuse) (Knie et al. 1983), and a 48 

hour LC50 of 138 mg/liter for bluegill (Lepomis macrochirus) (Turnbull et al. 1954).

Aquatic Invertebrate Toxicity
35

Acute toxicity to the freshwater invertebrate Daphnia magna was reported as 48 hour 

EC50 of 330 mg/liter (ABC Laboratories, 1982c). No effects were observed at 180 

mg/liter or lower concentrations. Test material concentrations were not measured. 

Dilution water was well water with total hardness of 255 mg/liter as CaCO3. Test 

temperature was 20oC with a 16-hour daylight photoperiod. As with the fish tests, a low 

pH (2.4) was associated with the highest concentration.

Other published scientific studies (Klimisch code 2C) found a significant difference when 

the test material was neutralized (Bringmann and Kuehn, 1982). The 24-hour EC50 results 

of a daphnid study are listed below:

 Maleic anhydride - Non-neutralized - 88 mg/liter

 Maleic anhydride - Neutralized - 5600 mg/liter

 Maleic acid - Non-neutralized - 83 mg/liter

This supports a hypothesis that acidity is a primary factor in the observed aquatic 

toxicity.

Aquatic Plant Toxicity

Toxicity to the freshwater alga Pseudokirchneriella subcapitata (formerly known as 

Selenastrum carpricornutum) found no effects on either growth or biomass after 72 hours 

at 150 mg/liter maleic anhydride (Springborn Smithers Laboratories 2002d). Arithmetic 

average concentration in the highest concentration (nominally 150 mg/liter) was 130 

mg/liter measured as maleic acid. Because no effects were observed in all concentrations, 

an EC50 can be estimated as > 130 mg/liter. Algae were grown and tested using AAP 

(Algal assay procedure medium) at 26oC under continuous illumination. Microscopic 

observations showed no abnormal cells in any treatment. Test stock solution was adjusted 

at test initiation from pH 2.9 to pH 7.5 using sodium hydroxide.

XI. RISK CHARACTERIZATION 

Exponent on behalf of Cheminova A/S. (1600 Wilson Boulevard, Suite 700, Arlington, 

VA 22209) is requesting that EPA to amend the established tolerance exemption from the 

requirement of a tolerance for maleic anhydride (CAS Reg. No. 108-31-6) to include use as an 

inert ingredient (stabilizer) in pesticide formulations applied to growing crops only in accordance 

with 40 CFR 180.920, at a maximum of 5% by weight in the pesticide formulation. 

Maleic anhydride is a multi-functional chemical intermediate with many industrial 

applications. The primary use of maleic anhydride is in the manufacture of polyester and alkyd 

resins. It is also used in the manufacture of lube oil additives, copolymers dye intermediates, 

pharmaceuticals, textile chemicals, fumaric and malic acid, and other organic compounds, and 

are approved for use as an indirect food additives by the U.S. Food and Drug Administration 

(FDA).

Maleic anhydride is readily hydrolyzed to maleic acid under aqueous conditions and is 
36

then hydroxylated to malic acid, which participates in the Krebs cycle or may be excreted 

unchanged or in conjugated form. 

Although no dermal absorption studies were available for maleic anhydride or maleic 

acid, a dermal absorption value was estimated using the ratio of an oral LD50 and a dermal LD50. 

The two studies used were the oral rabbit LD50 of 875 mg/kg and the dermal rabbit LD50 of 2620 

mg/kg maleic anhydride. The resulting estimated dermal absorption was 33%. 

The chronic reference dose (cRfD) of 0.1 mg/kg/day was determined on the basis of the 

NOAEL of 10 mg/kg/day from the 2-year oral toxicity study in rats. The LOAEL of 32

mg/kg/day is based on slight to marginal decreases in bodyweight. This endpoint was used for 

dietary and dermal exposures. The 6-month inhalation toxicity study with a NOAEL of 0.93 

mg/kg/day is used for inhalation exposures. The LOAEL of 1000 mg/kg/day is based on 

reduction in bodyweights and hyperplastic and metaplastic changes of nasal tissues. These 

studies provided the lowest NOAEL in the database (most sensitive endpoint) and also provides 

the most protective limits for potential human effects. An uncertainty factor (UF) of 100X (10-

fold for interspecies extrapolation and 10-fold for intra species variability) was applied to the 

NOAELs of 10 and 0.93 mg/kg/day to derive the cRfD for oral, dermal and inhalation exposure. 

This endpoint of concern was also used for all dermal and inhalation exposure scenarios. Dermal 

absorption was estimated to be 33%. The limit in formulation was reduced from 5% to 3.5% as 

requested by Exponent.

EPA has determined that reliable data show the safety of infants and children would be 

adequately protected if the FQPA SF were reduced to 1X. 

An acute dietary risk assessment was not conducted because no endpoint of concern 

following a single exposure was identified in the available studies. A chronic dietary exposure 

assessment was completed and performed using the Dietary Exposure Evaluation Model DEEMFCIDTM, Version 3.16. The chronic population-adjusted dose (cPAD) 0.1 mg/kg/day.

Based on analyses of estimated dietary risks for the general U.S. population and various 

population subgroups, the chronic dietary exposure estimates for maleic anhydride are below the 

Agency’s level of concern for the general U.S. population and all population subgroups. The 

chronic dietary exposure estimate is 13.3% of the cPAD for the general population and 49.4% of 

the cPAD for the highest exposed population subgroup, children 1-2 years old. 

The Agency’s level of concern (LOC) for occupational and residential dermal and 

inhalation exposures to maleic anhydride is 100 [i.e., a margin of exposure (MOE) greater than 

100 is not of concern to EPA]. The LOC is based on a 10X uncertainty factor (UF) to account 

for interspecies extrapolation to humans from the animal test species and 10X UF to account for 

intra-species sensitivity.

Outdoor residential applicator exposures were calculated using three exposure scenarios, 

low pressure handwand, hose end sprayer and trigger sprayer were assessed for each pesticide 

type, herbicide, insecticide and fungicide in both short- and intermediate-term scenarios. The 
37

combined outdoor residential applicator dermal and inhalation MOEs ranged from 280 to 1300. 

As the level of concern is for MOEs that are lower than 100, these MOEs are not of concern. 

Indoor residential applicator exposures were calculated using three exposure scenarios, 

mopping, wiping and aerosol spray were assessed in both short- and intermediate-term scenarios. 

The combined indoor residential applicator dermal and inhalation MOEs ranged from 97 to 

3600. The level of concern is for MOEs that are lower than 100. The MOE of 97 for indoor 

surface cleaner wiping is lower than the level of concern and is the only MOE to be below 100. 

However with all the conservatisms incorporated into this exposure estimate, this scenario is not 

expected to be of concern.

Post-application residential exposure to treated lawns was calculated to be 950 and 1900 

for adult short- and intermediate-term exposures respectively and 490 and 990 for children shortand intermediate-term exposures respectively. The post-application child (hand-to-mouth) shortterm MOE was calculated to be 4200 from treated lawns. As the level of concern is for MOEs 

that are lower than 100, these MOEs are not of concern.

Short-term aggregate exposure takes into account short-term residential exposure plus 

chronic exposure to food and water (considered to be a background exposure level). Maleic 

anhydride may be used as an inert ingredient in pesticide products that could result in short-term 

residential exposure. The Agency has determined that it is appropriate to aggregate chronic 

exposure through food and water with short-term residential exposures. Using the exposure 

assumptions described in Section IV, EPA has calculated the combined short-term aggregated 

food, water, and residential exposures. The adult short-term aggregate MOE was calculated to be 

112 for both males and females. Adult aggregate MOE combines average food and water 

exposure from the chronic dietary exposure with high end residential applicator exposure (liquid 

trigger sprayer). As the level of concern is for MOEs that are lower than 100, this MOE is not of 

concern. EPA has concluded the combined short-term aggregated food, water, and residential 

exposures results in an aggregate MOE of 105 for children. Children’s aggregate MOE combines 

average food and water exposure from the chronic dietary exposure with residential exposure 

associated with contact with treated lawns (post-app dermal exposure + hand-to-mouth + objectto-mouth). As the level of concern is for MOEs that are lower than 100, these MOEs are not of 

concern.

Intermediate -term aggregate exposure takes into account intermediate-term residential 

exposure plus chronic exposure to food and water (considered to be a background exposure 

level). Maleic anhydride may be used as an inert ingredient in pesticide products that could result 

in intermediate-term residential exposure. The Agency has determined that it is appropriate to 

aggregate chronic exposure through food and water with intermediate-term residential exposures. 

Using the exposure assumptions described in Section IV, EPA has calculated the combined 

intermediate-term aggregated food, water, and residential exposures. The adult intermediate-term 

aggregate MOE was calculated to be 178 for both males and females. Adult aggregate MOE 

combines average food and water exposure from the chronic dietary exposure with high end 

residential applicator exposure (liquid trigger sprayer). As the level of concern is for MOEs that 

are lower than 100, this MOE is not of concern. EPA has concluded the combined intermediateterm aggregated food, water, and residential exposures results in an aggregate MOE of 119 for 
38

children. Children’s aggregate MOE combines average food and water exposure from the 

chronic dietary exposure with residential exposure associated with contact with treated lawns 

(post-app dermal exposure + hand-to-mouth + object-to-mouth). As the level of concern is for 

MOEs that are lower than 100, these MOEs are not of concern.

Occupational handler risks are not of concern for all scenarios. It is noted that this 

occupational handler assessment assumes that mixer/loader/applicators are wearing gloves and 

not wearing protective respirators when using open pour loading in support of aerial and 

groundboom application. The combined occupational handler combined dermal and inhalation 

MOEs ranged from 460 to 4500. The estimated MOEs are greater than 100 therefore the 

occupational MOEs are not of concern. 

Occupational post-application risks are not of concern for all scenarios. It is noted that 

this occupational post-application assessment assumes default 20% dislodgeable foliar residue. 

The estimated MOEs are greater than 100 based. The lowest estimated MOE was 110, based on 

hand harvesting, leaf pulling, thinning, pruning, training/tying grapes. As the level of concern is 

for MOEs that are lower than 100, these MOEs are not of concern.

Maleic anhydride is not persistent in the environment and is not expected to

bioaccumulate. In the presence of water, maleic anhydride rapidly hydrolyzes to form maleic 

acid. The half-life of maleic anhydride in air is estimated to be 4.2 to 16 hours; due primarily to 

direct reactions with photochemically generated hydroxyl radicals. Maleic anhydride and maleic 

acid are readily biodegraded under aerobic conditions in sewage sludge, and are expected to 

biodegrade in soil and water as well. Fugacity-based fate and transport modelling suggest that 

maleic anhydride, hydrolyzed to maleic acid in water and under humid conditions, will partition 

primarily to water. 

Based on the low toxicity to fish, trout (Salmo gairdneri) and bluegill (Lepomis 

macrochirus), freshwater aquatic invertebrate, Daphnia magna, and the lack of inhibition on 

growth of the unicellular algae, Pseudokirchneriella subcapitata, effects of concern to nontarget 

aquatic species resulting from the use of maleic anhydride as an inert ingredient is not 

anticipated. 

Potential areas of environmental justice concerns, to the extent possible, were considered 

in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal 

Actions to Address Environmental Justice in Minority Populations and Low-Income 

Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.

Taking into consideration all available information on maleic anhydride EPA concludes 

that there is a reasonable certainty that no harm to any population subgroup will result from 

aggregate exposure to maleic anhydride when considering residential, occupational, dietary 

exposure and all other non-occupational sources of pesticide exposure for which there is reliable 

information. Therefore, the establishment of an exemption from the requirement of a tolerance 

under 40 CFR 180.920 for residues of maleic anhydride (CAS Reg. No. 108-31-6) when used as 

a pesticide inert ingredient (stabilizer) applied to growing crops at a maximum of 3.5% in 

pesticide formulations can be considered safe under section 408(q) of the FFDCA.
39

REFERENCES

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Unpublished Report No. AB-82-195. Submitted to USEPA by Monsanto Company as EPA Doc. 

No. 878214781.

ABC Laboratories, Inc. (1982b) Acute Toxicity of Maleic Anhydride to Bluegill Trout. 

Unpublished Report No. AB-82-196. Submitted to USEPA by Monsanto Company as EPA Doc. 

No. 878214782.

ABC Laboratories, Inc. (1982c) Acute Toxicity of Maleic Anhydride to Daphnia magna. 

Unpublished Report No. AB-82-187. Submitted to USEPA by Monsanto Company as EPA Doc. 

878214780.

Bearman, S. L. (1990) Letter from Huls America Inc. to USEPA regarding the enclosed list of 

studies on Isopropanol, 2-ethyl-1-hexanol, methyl isobutyl ketone and maleic anhydride. Huls 

America Inc., Piscataway, NJ. Unpublished Report No. 86-900000467. Submitted to EPA by 

Huls America Inc. as EPA Doc. No. 86-900000467.

Bringmann, G., and Kuehn, R. (1982) Ergebnisse der Schadwirkung wassergefaehrdender Stoffe 

gegen Daphnia magna in einem weiterentwickelten standardisierten Testverfahren. Z. Wasser 

Abwasser Forsch. 15: 1-6.

CIIT (1983) Chronic Dietary Administration of Maleic Anhydride. Prepared for CIIT, Research

Triangle Park, NC. IITRI Report No. IITRI-L8026-6B.

Fitzhugh, O. G., and Nelson, A. A. (1947) The comparative chronic toxicities of fumaric, 

tartaric, oxalic, and maleic acids. J. Amer. Pharm. Assoc. 36: 217-219.

Goldenthal, E. I., Jessup, D. C., and Geil, R. G. (1979a) Four-Week Inhalation Research and

Development Corporation, Mattawan, MI. Unpublished Report No. 401-015. Submitted to 

USEPA by Monsanto Company, EPA Doc. No. 878214771.

Goldenthal, E. I., Jessup, D. C., and Rodwell, D. E. (1979b) Teratogenic Study of Maleic 

Anhydride in Rats. International Research and Development Corporation, Mattawan, MI. 

Conducted for Monsanto Company. Report No. 401-013.

Haworth, S. T., Lawlor, K., Mortelmans, K., Speck, W., and Zeiger, E. (1983) Salmonella

mutagenicity test results for 250 chemicals. Environ. Mutagen. Suppl. 1: 3-142.

Hazleton Laboratories America, Inc. (1983) In vivo Bone Marrow Chromosome Study in Rats

(Inhalation Exposure). Unpublished Report No. 241-142. Submitted to USEPA by Monsanto

Company as EPA Doc. No. 878214783.

HSDB (Hazardous Substances Data Bank). 2006. U.S. National Library of Medicine, National 

Institutes of Health, Bethesda, MD. http://toxnet.nlm.nih.gov/. 
40

Hüls AG (1988b) Verlaengerter Toxizitaetstest bei Daphnia magna nach UBA. PS-499/871130. 

Biologie/Toxikologie, Biologie II, 1 S.

Hüls AG (1988a) Mutagenitaetsuntersuchung von Maleinsaeureanhydrid mit Hilfe des 

Salmonella typhimurium/Mikrosomen-Mutagenitaets-Tests nach Ames. Unpublished Report No. 

88/010.

Humiston, C. G., and Quest, J. F. (1977) A Supplemental Toxicological Study of Maleic 

Anhydride Incorporated in the Diet of Male Rats for 183 Days. Dow Chemical Company Report 

No. D-001251. Submitted to the USEPA by Dow Chemical Company. EPA Doc. No. 

#878214749

Humiston, C. G., Frauson, L. A., Quast, J. F., and Wade, C. E. (1975a) Maleic Anhydride: 

Results of a 90-Day Dietary Feeding Study in Rats. Dow Chemical Company Report No. D1248. Submitted to USEPA by Dow Chemical Company, EPA Doc. No. #878214746.

Humiston, C. G., McCollister, S. B., Kociba, R. J., and Wade, C. E. (1975b) 90-Day Dietary 

Feeding Studies on Maleic Anhydride in Beagle Dogs. Dow Chemical Company Report No. D001249. Submitted to USEPA by Dow Chemical Company. EPA Doc. No. #878214747.

IRDC (1982) Three Generation Reproduction Study in Rats (Modified to a Two Generation 

Study). International Research and Development Corporation, Mattawan, MI. Unpublished 

Report (No.401-089a). Submitted to USEPA by Monsanto Company as EPA Doc. No. 

878214777.

Ishidate, M., and Yoshikawa, K. (1980) Chromosomal aberration tests with Chinese hamster 

cells in vitro with and without metabolic activation – A comparative study on mutagens and 

carcinogens. Arch. Toxicol. Suppl. 4: 41-44.

Ishidate, M., Sofuni, T., and Yoshikawa, K. (1981) Chromosomal aberrration tests in vitro as a 

primary screening tool for environmental mutagens and/or carcinogens. Gann. Monogr. Cancer 

Reg. 27: 95-108.

Kawachi, T., Yahagi, T., Kada, T., Tazima, Y., and Ishidate, M. (1980) Cooperative Programme 

on Short-Term Assays for Carcinogenicity in Japan. Ministry of Health and Welfare, pp. 323-

330.

Knie, J. A., Halke, I., and Schiller, W. (1983) Ergebnisse der Untersuchungen von chemischen 

Stoffen mit vier Biotests. Dtsch. Gewasesserkdl. Mitt. (DGM) 27: 77-79.

Lake, R. S., DeVito, G. L., , Szot, R. J., and Schwartz, E. (1988) Nonmutagenicity of maleic acid 

and its sodium salts in Salmonella assays. Mutat. Res. 207: 1-5.

OECD SIAP. 2004, SIDS Initial Assessment Profile (SIAP) for Maleic Anhydride and Maleic 

Acid. Summary of SIDS Submission to the Organization for Economic Cooperation and 
41

Development (OECD) High Production Volume Chemicals Program. April, 2004. http://cs3-

hq.oecd.org/scripts/hpb/.

Short, R.D., Johannsen, F. R., and Ulrich, C. (1988) A 6-month multispecies inhalation study 

with maleic anhydride. Fundam. Appl. Toxicol. 10: 517-524

Short, R. D., Johannsen, F. R., Levinskas, G. J., Rodwell, D. E., and Schardein, J. L. (1986)

Teratology and multigeneration reproduction studies with maleic anhydride in rats. Fundam. 

Appl. Toxicol. 7: 359-366.

Springborn Laboratories (2001a) Maleic Anhydride – Determination of the Melting Point.

Conducted for the American Chemistry Council Maleic Anhydride Panel. Unpublished Report, 

Springborn Study No. 13761-6101.

Springborn Laboratories (2001b) Maleic Anhydride – Determination of the Boiling Point. 

Conducted for the American Chemistry Council Maleic Anhydride Panel. Unpublished Report, 

Springborn Study No. 13761.6102.

Springborn Laboratories, Inc. (2001c) Maleic Anhydride – Determination of the 

Biodegradability by the CO2 Evolution Modified Sturm Test. Conducted for the American 

Chemistry Council Maleic Anhydride Panel. Unpublished Report No. 13761.6106.

Springborn Smithers Laboratories (2002a) Maleic Anhydride – Determination of Vapor 

Pressure. Conducted for the American Chemistry Council Maleic Anhydride Panel. Unpublished 

Report, Springborn Smithers Study No. 13761.6103

Springborn Smithers Laboratories (2002b) Maleic Anhydride – Determination of the nOctanol/Water Coefficient. Conducted for the American Chemistry Council Maleic Anhydride

Panel. Unpublished Report, Springborn Smithers Study No. 13761.6108

Springborn Smithers Laboratories (2002c) Maleic Anhydride – Determination of Water 

Solubility at pH 4, pH 7, and pH 9. Conducted for the American Chemistry Council Maleic 

Anhydride Panel. Unpublished Report, Springborn Smithers Study No. 13761.6107.

Springborn Smithers Laboratories (2002d) Maleic Anhydride and its Sodium Salts – Toxicity to 

the Freshwater Green Alga, Pseudokirchneriella subcapitata. Conducted for the American 

Chemistry Council Maleic Anhydride Panel. Unpublished Report. Springborn Smithers Study 

No. 13761.6109.

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fresh water fish. Industr. Engineer. Chem. 46: 324-333.

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chemicals in turbid waters. Sewage Industr. Wastes 29: 695-711.
43

APPENDIX

US EPA Ver. 3.16, 03-08-d

DEEM-FCID Chronic analysis for DEEM RESIDUE FILE FOR IN-10771 1X SF APPLES 4PPM

 NHANES 2003-2008 2-day

Residue file name: C:\Users\dlieu\Documents\EPA RD Pesticides\Inerts\Maleic Anhydride\2014 

Assessment 180.920\DEEM Residue File for IN-10771 1X SF Apples 4ppm.R08

 Adjustment factor #2 used.

Analysis Date 03-28-2016/11:26:28 Residue file dated: 03-28-2016/11:25:21

Reference dose (RfD, Chronic) = .1 mg/kg bw/day

COMMENT 1: Inert 57 active ingredients + drinking water (100ppb)

===============================================================================

 Total exposure by population subgroup

-------------------------------------------------------------------------------

 Total Exposure

 -----------------------------------

 Population mg/kg Percent of 

 Subgroup body wt/day Rfd 

-------------------------------------- ------------- ----------------

Total US Population 0.015922 15.9%

Hispanic 0.018412 18.4%

Non-Hisp-White 0.015313 15.3%

Non-Hisp-Black 0.015396 15.4%

Non-Hisp-Other 0.018832 18.8%

Nursing Infants 0.025705 25.7%

Non-Nursing Infants 0.047627 47.6%

Female 13+ PREG 0.013677 13.7%

Children 1-6 0.053678 53.7%

Children 7-12 0.019914 19.9%

Male 13-19 0.010833 10.8%

Female 13-19/NP 0.011222 11.2%

Male 20+ 0.010839 10.8%

Female 20+/NP 0.011709 11.7%

Seniors 55+ 0.011677 11.7%

All Infants 0.040859 40.9%

Female 13-50 0.011385 11.4%

Children 1-2 0.072389 72.4%

Children 3-5 0.046364 46.4%

Children 6-12 0.022157 22.2%

Youth 13-19 0.011039 11.0%

Adults 20-49 0.011143 11.1%

Adults 50-99 0.011602 11.6%

Female 13-49 0.011376 11.4%

-------------------------------------------------------------------------------
44

Estimation of Maximum Residues On Apples For An Inert Ingredient with a 21-day preharvest 

interval (PHI).

The inert ingredient dietary exposure model default residue level for apples and apple commodities is 25 ppm based on highest

active ingredient tolerance (captan). Below are the all the current tolerances (at least as of 2012) for active ingredients on 

apples.

In considering these data, all of the established tolerances for apples that exceed 4 ppm are for active ingredients that have 

either post-harvest use on apples or have uses with relatively short (7 days or less) PHIs. Therefore it is reasonable to assume, 

as a worst-case, that the use of a pesticide product with a 21-day PHI on apples would not result in inert ingredient residues in 

excess of 4 ppm. This value is further supported by actual monitoring data for pesticides on apples such as the USDA Pesticide 

Data Program Calendar Year 2014 Annual Summary 

https://www.ams.usda.gov/sites/default/files/media/2014%20PDP%20Annual%20Summary.pdf in which no pesticide residue 

was detected on apples at concentrations in excess of 4.2 ppm.

180.449 Apple 0.02 Avermectin B1 and its delta-8,9-isomer

180.502 Apple 0.08 Aviglycine (Aminoethoxyvinylglycine

hydrochloride)

180.103 Apple 25 Captan

180.342 Apple 0.01 Chlorpyrifos

180.446 Apple 0.5 Clofentezine

180.153 Apple 0.5 Diazinon

180.231 Apple 0.5 Dichlobenil

180.106 Apple 0.1 Diuron

180.172 Apple 5 Dodine

180.533 Apple 1 Esfenvalerate

180.300 Apple 5 Ethephon

180.421 Apple 0.3 Fenarimol

180.632 Apple 0.2 Fenazaquin

180.480 Apple 0.4 Fenbuconazole

180.362 Apple 15 Fenbutatin-oxide (Hexakis (2-methyl-2-phenylpropyl)distannoxane, Fenbutatin-oxide

180.114 Apple 4 Ferbam

180.574 Apple 2 Fluazinam

180.661 Apple 0.3 Fluopyram

180.276 Apple 0.5 Formetanate hydrochloride

180.473 Apple 0.05 Glufosinate amrnonium

180.472 Apple 0.5 Imidacloprid

180.111 Apple 8 Malathion

180.176 Apple 7 Mancozeb

180.408 Apple 0.2 Metalaxyl

180.253 Apple 1 Methomyl

180.217 Apple 0.5 Metiram

180.443 Apple 0.5 Myclobutanil

180.356 Apple 0.1 Norflurazon

180.129 Apple 25 O-Phenylphenol and its sodium salt

180.303 Apple 2 Oxamyl

180.337 Apple 0.35 Oxytetracycline

180.261 Apple 10 Phosmet (N-(Mercaptomethyl) phthalimide 5- (O,O-dimethyl phosphorodithioate) and its oxygen

analog)

180.317 Apple 0.1 Propyzamide

180.494 Apple 0.5 Pyridaben

180.213 Apple 0.2 Simazine

180.482 Apple 1 Tebufenozide

180.209 Apple 0.3 Terbacil

180.371 Apple 2 Thiophanate-methyl

180.132 Apple 7 Thiram

180.476 Apple 0.5 Triflumizole

180.116 Apple 7 Ziram