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 Considera tions 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 ASSE SSMENT

................................ ................................ ............. 26

i. Acute Dietary Risk.

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

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

................................ .................... 27

iv. S hort

- term Aggregate Risk.

................................ ................................ .............. 27

v. Intermediate

- Term Aggregate Risk.

................................ ................................ .. 27

VI. OCCUPATIONAL EXPOSURE/RISK PATHWAY

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

................................ ................................ ................... 28

B. Occupational Post

- A pplication 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

................................ ................................ ................................ ................................ ... 433

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 inc l ude 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 manufactu re 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 r epeat 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/m 3 (0, 0.3, 0.8, and 2.4 ppm) maleic anhydride for six months. Body weights were decreased in rats a t 3.3 and 9.8 mg/m 3 ( 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/ m 3 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 irritati on in this study was 3.3 mg/m 3 or 0.93 mg/kg/day based on localized eye/nasal irritation effects seen at the
LOAEL of 9.8 mg/m 3

. The NOAEL for systemic toxicity in rats , hamsters and monkeys is 9.8 mg/m 3 ; the highest dose tested

.

In a 28

- day inhalation s tudy with maleic anhydride in Sprague

- Dawley rats, e vidence of nasal and ocular irritation (concentration

- dependent) occurred at 12, 32 and 86 mg/m 3 . Reduced body weight gain and food consumption as well as increased incidence of hemorrhagic lung foci

occu rred at 32 and 86 mg/m 3

. The NOAEL for the systemic toxicity is 12 mg/m 3 (3 ppm) based on the reduced body weights and food consumption seen at the LOAEL of 32 mg/m 3

.

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 nephro sis 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 th ere 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 t he 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 a n oral (gavage) d evelopmental 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 F 0 and F 1 parental animals and m aleic 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

e ffects on litter size and on pup survival were observed at the dose of 55 mg/kg/day and above in
the F 2 litters. Maleic anhydride was toxic to parental animals in all dose groups. For parental toxicity th e LOAEL was 20 mg/kg/day. A NOAEL for parental toxic ity 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 anhydrid e 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/k g/day ma leic 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

- 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 o f 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 LD 50 and a dermal LD 50

. The two studies used were the oral rabbit LD 50 of 875 mg/kg and the dermal rabbit LD 50 of 2620 mg/kg male ic anhydride . The resulting estimated dermal absorption was 33%.

The chronic r eference d ose (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 i s based on
reduction in bodyw eights and hyperplastic and metaplastic changes of nasal tissues. These
studies provided the lowest NOAEL in the database (most sensitive endpoint) and also provide s the most protective limits for potential human effects. An uncertainty factor ( U F ) of 100X (10

- fold for interspecies extrapolation and 10

- fold for intra species variability) was applied to the
NOAEL s 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 de rmal and inhalation exposure scenarios. D ermal 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
ade quately protec ted if the FQPA SF were reduced to 1X.

An a cute 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 DEEM

FCID TM , Version 3.16. The chronic population

- adjusted dose (cPAD) 0.1 mg/kg/day.

Based on analyses of estimated dietary risks for the gene ral 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 i s 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
int ra

- species sensitivity.

Outdoor residential applicator exposures were calculated using t hree exposure scenarios, low pressure handwand, hose end sprayer and trigger sprayer were assessed for each pesticide6

type, herbicide, insecticide and fungicide in b oth 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
360 0. 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 calculat ed to be 950 and 1900
for adult short

- and intermediate

- term exposures respectively and 490 and 990 for children short

and intermediate

- t erm exposures 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.

Short

- term aggregate exposure t akes 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 aggreg ated 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 die tary 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.

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 resul t 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 t he 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, w ater, and residential exposures results in an aggregate MOE of 1 19 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 wear ing 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 a re 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

- ap plication 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 concer n 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

- l ife of maleic anhydride in air is estim ated 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 t o 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 spec ies 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 O rder 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 inf ormation on maleic anhydride EPA conclu des that there is a reasonable certainty that no harm to any population subgroup will result from

aggreg ate exposure to maleic anhydride when considering residential, occupation al , 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 180.92 0 for residues of maleic anhydride (CAS Reg. No. 108

- 31

- 6) when used as8

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 formula tions applied to growing

crops in accordance with 40 CFR 180.9 2 0 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 additive s, 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 e asier 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 an d 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 C 4 H 2 O 3 C 4 H 4 O 4 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 K ow ) 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*m 3 /mole at 25°C) 3.93 x 10

- 6 * 7x10

- 14

*Extrapolated/EstimatedIII. 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 tabl e 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 ho urs 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 p ig. 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 non

irritating 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 p igs 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 anh ydr ide

- 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 Tox icity Profile of Maleic Anhydride and Maleic Acid

Study Type Results MRIDs # /Reference
Acute Oral

– rat , mouse, rabbit guinea pig LD 50 ( rat) = 400 to 1050 mg/kg
LD 50 (mouse) = 465mg/kg
LD 50 (rabbit) = 875 mg/kg
LD 50 (guinea pig) = 390 mg/kg OECD SIDS 2004
HSDB 2006 (Lewis et al. 1996)

Acute Dermal

– rabbit LD 50 (rabbit) = 1600 mg/kg maleic acid
LD 50 (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 I rritating OECD SIDS 2004

Primary Skin Irritation

– rabbit Severely Irritating OECD SIDS 2004

Dermal Sensitization

– guinea pig Maleic Anhydride: Skin sensitizer
Mal e ic 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/m 3 (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 d ecreased only in the high

exposure 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 we re 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 ch anges 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 irritatio n and judged to be reversible. The NOAEL for irritation in this study was 3.3 mg/m 3 or 0.93 mg/kg/day based on localized eye/nasal irritation effects seen at the LOAEL of 9.9 mg/m 3

. The NOAEL for systemic toxicity in rats, hamsters and monkeys is 9.8 mg/m 3 , the highest dose tested . ( Short et al., 1988 ).12

In another repeat dose inhalation study, m ale and female Sprague

- Dawley rats were exposed by inhalation (whole body) to 0, 12, 32, or 86 mg/m 3 (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 effe cts occurred at lower concentrations. Reduced body weight gain (both sexes) and food consumption (females only) occurred at 32 and 86 mg/m 3

. 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 hype rplasia 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

- m oderate. 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/m 3 (3 ppm)

.

In a 90

- day repeat dose dietary study, m ale 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. Th ese 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 fro m 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 treat ment 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 marke d 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 staining13

casts, granular degeneration of the epith elial 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 t he 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, m ale 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 toxicit y, which was evidenced by small (<6%), but dose

- related, decrease in body weights of male rats fe d 32 and 100 mg/kg/day compared to the controls. The
female rats fed 32 and 100 mg/kg/day also ha d 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. 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 th at 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, d ogs were fed in the diet 0, 20, 40, or 60 mg maleic anhydride/kg/day, seven days a week for 90 days. Food intake w as 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 significant14

effects on body weight gains at any interval. Dams from all test groups produced normal

sized litters, with no evidence of post

- implantation loss. Fetal body weights in all

trea tment 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 wa s 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 fro m 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 sin ce 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 F 1 litters or up to 55 mg/kg /day in the F 2 litters. Maleic anhydride was toxic to parental animals in all dose groups. Significant mortality occurred in the F 0 and F 1 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 F 1 (and to minor extent in the F 0 ) adults and the incidence and severity appeared to increase with dose. In the high

- dose group F 0 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. F 1 generation showed a similar pattern of depressed weight gain; however, only
the F 1 males in the high

- dose group had statistically significant body weight depression at 30 weeks. Microscopic examination of tissues for F 0 adults revealed compound

- related
cha nges 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 F 0 group. In the F 1 generation, the absolute kidney weights of adult fema les 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

t oxicity 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 anhydr ide is rapidly hydrolyzed to maleic acid in the body, particularly by the oral route of exposure.

Mutagenicity and Genotoxicity15

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 nega tive ( 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 ). Ma leic 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 resulte d 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 th e 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, m ale 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 hi gh 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 a nd 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 th is 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 reta rded 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 i mmunotoxicity 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 conditi ons. 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 acry lating with amino acids, resulting in an immu n ological response (dermal and respiratory sensitization ( OECD SIDS 2004 ).

In a metabolism study, dogs were fed 60 m g/kg/day maleic anhydride for 9 0 days. Using a one compartment model, uptake rate and elimina tion 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 LD 50 and a
dermal LD 50 . The two studies used were the oral rabbit LD 50 of 875 mg/kg and the
dermal rabbit LD 50 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 inhalation

rats

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 intra

alveolar hemorrhage in lung OECD SIDS 2004 Goldenthal, 1979a17

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/m 3 or 0.93

mg/kg/day for rats , hamsters and monkeys
LOAEL (irritation) 9.8 mg/m 3 based on localized eye/nasal irritation

NOAEL (systemic) 9.8 mg/m 3 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 15 0 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 no ted 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 I nhalation 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 viv o mammalian (rat) bone marrow
chromosomal
aberration test

Maleic anhydride N/A Negative OECD SIDS 200418

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 f or dermal exposure scenarios based on an
estimation of the ratios between an oral and dermal LD 50 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/m 3 or 0.93 mg/kg/day based on localized eye/nasal irritation effects seen at the LOAEL of 9.8 mg/m 3

. Since the major effect of maleic anhydride is irritation via inhalation, this endpoint is protective of any systemic toxicit y seen at concentrations of 32 mg/m 3 and above seen in the 28

- day inhalation toxicity study . An uncertainty f actor of 100x was applied, 10x for interspecies variability and 10x for intraspecies variability.

T able 4 . Summary of Toxic ological 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
UF A = 10 x UF H = 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

T able 4 . Summary of Toxic ological 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 short

term (1 to 30 days) NOAEL= 10 mg/kg/day
UF A = 10 x UF H = 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
UF A = 10 x UF H = 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

a bsorption rate = 33 %)
UF A = 10 x UF H = 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%)
UF A = 10 x UF H = 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

.

UF A = extrapolation from a nimal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (i ntraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = 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 do se. 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 data base is considered as adequate for FQPA assessment.20

ii. There is no evidence of increased susceptibility of infants and children due to pre

and post

- natal exposure to maleic an h ydride. 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 developme ntal toxicity study in rabbits.

iii. There is no indication that maleic anhydride is neurotoxic chemical s

. 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 avail able studies, therefore there is no need for additional UFs to account for immunotoxicity.

v. The dietary food exposure assessment utilizes proposed tolerance leve l 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 request ed 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 e xposure or risk assessments regarding human occupational or residential

exposure. Resources con straints prohibit the Agency fro m conducting monographic, “all

inclusive” assessments of exposure for all possible or imaginable combinations of methods of appli cation 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 method s of application and
site s 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 o n a given commodity. As to residue levels in food, n o 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 e stimates 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 insecticide s, herbicides, and fungicides. A complete description of the general approach taken to

ass ess 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.” (D3617 07, 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 f or 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 maxim um residue values for apples and apple commodities resulting from th e 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 pr ovided 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 appl es 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 t olerance for a given commodity. Implicit in this assumption is that there would be similar rates of degradation (if any) between the22

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 seri es of compounded
conservatisms. First, assuming that the level of residue for an inert ingredient is equal to the level of residue for the active ingre dient 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 le vel of inert ingredient residues is the active ingredient wit h 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

o f 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 a t 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 poss ible for an active ingredient. In summary, EPA chose a very conservative method for estimat ing 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 al l 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 quanti fy 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 Chron ic 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 leve l of concern for all supported commodities. The chronic dietary exposure estimate for the highest exposed population subgrou p, children 1

- 2 years old is 72.4 % of the chronic population adjusted dose (cPAD). The chronic dietary exposure estimate for the ge neral 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 genotox icity stud ies 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; Memorand um 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/O ffice of Pesticide Programs. T he 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 fo rm, exposure is assessed as follows:

Unit Exposure * Amount applied/Unit * Units treated/day * absorption f actor ÷ 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%. T he 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 meas ure of risk). An MOE is calculated by dividing the value of the average daily dose into the toxicological endpoint of concern (also expre ssed in mg material/kg /day). Typically, result ing 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 t he 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

- mont h 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

e xposure are pre sented as summaries for residential “handlers” (non

- occupationally associated applicators) and for oc cupational pesticide handlers. Since lawn and turf uses may be involved, assessments of post

- application exposures to “ residents” were also
conducted. Esti m ated exposure doses as well as margins of exposure are presented for
inhalation , dermal and incidental oral exposure. Post

- application oral exposures (hand

- to

mouth 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 route s 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 typi cal 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. T he Agency conducted an assessment to represent worse

- cas e 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 Rate 1 Exposed

Populatio
n & Exposure
Duration 2 Dermal

Dose ( mg/kg/da y) 3 Inhalation

Dose (mg/kg/da y) 3 Derm

al
MOE 4 Inhalati

on MOE 4 Total

Combin
ed
MOE 5

Herbicid
e/ Fungicid

e /
Insectici
de Liquids/Low

Pressure
Handwand

0. 0 31 5

lb/gal Short &

Intermedi
ate Term 0. 0 24688 0. 0000059 410 160,000 400

Liquids/Hos
e End Sprayer Short &
Intermedi
ate Term 0. 0 07147 0. 0000335 1400 28 ,000 1300

Liquids/Trig ger Sprayer

HG, IS,
C&C Short &
Intermedi

ate Term 0. 0 35083 0. 0000037 290 250 ,000 28025

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 d efault values provided in the AD assessment tool

. I nert 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 sc enario) * 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 trig ger sprayer were assessed for each pesticide 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.

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

- A pplication Short

- and Intermediate

- term Exposures and Risks for Maleic Anhydride and Maleic Acid
Pesticide Type Exposure Scenario Application
Rate 1 Exposed Population &

Exposure Duration 2 Daily Dose (mg/kg/day) 3 MOE 4

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. I nert ingredient limited to 3. 5 % of formulation.

2 ST and IT indicate short

- or intermediate

- term exposure durations

3 Daily Dose i s 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 treate d lawns was calculated to be 950 and 1900 for adults respectively and 490 and
99 0 for children respectively

. The post

- application child (hand

- to

- mouth) short

- term MOE was calculated to be 42 00 from treated lawns

. A s 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 app ropriate safety factors (SFs). EPA calculates the aPAD and cPAD by dividing the POD (i.e. toxicological end point) 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 a pplicable UFs is not
exceeded.

i. Acute Dietary Risk. An acute aggregate risk assessment takes into account exposure estimates from acute dietary consumpt ion of food and drinking water using the exposure assu mptions
discussed in S ection IV for acute exposure. However there was no hazard attributable to a single exposure seen in the toxicity database fo r 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 exp osure assumptions
discussed in S ection IV from chronic exposure. The chronic analysis was based on a 2

- year oral to xicity 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 f ro m 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 n ot 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 w ith short

- term residential exposures. Using the exp osure assumptions described in S ection IV, EPA has
calculated the combined short

- term aggregated food, w ater, 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

expo sure 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 Aggreg ate Risk Calculations for Maleic Anhydride and Maleic Acid

Population PoD

mg/kg/day LOC 1 Max
Allowable Exposure 2 mg/kg/day Average

Food &
Water Exposure 3 mg/kg/day Residential

Exposure 4 mg/kg/day Aggregate

MOE (food and residential) 5

Adult 10 100 0.10 0. 0 1 5922 0. 07312 11 2

Child 10 100 0.10 0. 0 72389 0. 0 2315 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 + Resi dential 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 anhydr ide 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 intermediat e

- term residential exposures. Using the exposure assumptions28

described in Section IV, EPA has calculated the combined intermediate

- term aggregated food, w ater, 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 chro nic 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. I ntermediate

- Term Aggregate Risk Calculations for Maleic Anhydride and Maleic Acid

Population PoD

mg/kg/day LOC 1 Max
Allowable Exposure 2 mg/kg/day Average

Food &
Water Exposure 3 mg/kg/day Residential

Exposure 4 mg/kg/day Aggregate

MOE (food and residential) 5

Adult 10 100 0.10 0. 015922 0.04041 17 8

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. O CCUPATIONAL 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 fungi cide/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 Exposure29

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 A gency. The quantitative exposure/risk assessment developed for occupational handlers to support the requested exemption for the inert ingredient based on scenarios to represent t he 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 materi al per lb of material handled. Unit

Exposures are derived in the Pesticide Handlers Exposure Database (PHED) and are recently summarized in the “Occupation Pes ticide 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 fact or

- - 100 % default for inhalation routes of exposure and

an estimated 33% for dermal route of exposure

BW Body Weight

- - 80 kg f or combined adults in the U.S. Taken from “Use
of New Human Body Weight Data as Presented in the EPA’s Exposure

F actors Handb ook: 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 occupat ional 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 Exposure 1 Application

Rate 1
lb inert/unit Units

Treated 1 Avg. Daily

Exposure 2 MOE 330 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 ) * Un its Treated * Absorption Rate÷
8 0 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
0.0 0126 Dermal:

1 300
Inhalation:
740
Combined:
460

Liquids: Airblast Dermal: Single

- layer gloves
0.0 23
Inhalation: No respirator
0.0012 0.315 lb ai/A

Nut Trees (Max/ST) 40 A/day Dermal: Single

- layer gloves
0.0 0 120
Inhalation: No respirator
0.00 0 19 Dermal:

8400
Inhalation:
4900
Combined:
3100

Liquids:
Groundboom Dermal: Single

- layer gloves
0.0 23
Inhalation: No respirator
0.0012 0.07 lb ai/A

Corn (Max/ST) 200 A/day Dermal: Single

- layer gloves
0. 0 0133
Inhalation: No respirator
0.0 0 0 21 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. 0 1247
Inhalation: Open Cab
0. 0 0071 Dermal:

800
Inhalation:
1300
Combined:
500

Liquid: Groundboom Dermal: Single

- layer gloves
0.0 14
Inhalation: Open Cab
0. 000 74 0.07 lb ai/A

Corn (Max/ST) 200 A/day Dermal: Single

- layer gloves
0. 0 0081
Inhalation: Open Cab
0.0 0 0 1 3 Dermal:

12000
Inhalation:
7200
Combined:
4500

Insecticide Mixer/Loader/Applicator Liquid: Low
Pressure handwand Dermal: Single

- layer gloves
0. 43
Inhalation:
No r espirator
0.030 0.252 lb ai/A

Ornamentals (Max/ST) 5 A/day Dermal: Single

- layer gloves
0. 0 0223
Inhalation: No respirator
0.00 0 47 Dermal:

4500
Inhalation:
2000
Combined:
140031

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 toxicologi cal PoD. Occupational handler risks are not of concern

. The Agency’s level of concern for inhalation and der mal exposure is for MOEs <100. The combined occupational handler combined dermal and inhalation MOEs ranged from
460 to 4500 . As the level of conce rn 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 ref erred

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 sc outing for pests or harve sting. 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 che mical’s degradation properties. In addition, the timi ng 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 short

term (1

- 30 days ). The following convention is used to estimate post

- application agricultural worker exposure.

DFR t = 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 (uni tless) (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 μ g for the DFR value (4.54E8 μ g/lb) CF3 = Area unit conversion factor to convert the surface area units (ft 2 ) in the application

rate to cm 2 for the DFR value (1.08E

- 3 ft 2 /cm 2 or 2.47E

- 8 acre/cm 2 )32

Average Daily Dose (ADD) (mg inert/kg/day) = DFR μ g/cm2 * TC cm2/hr * hr /day * 0.001 mg/ μ g * 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 Postappl i c ation Risk Assessment Calculator Version 2 (12/2008)

2. Dislodgeable foliar residue = Fraction of inert retained on foliage * Ap plication Rate (corrected for 3. 5 % limitation) * (1

- daily dissipation) t * conversion factors

3. S hort

- term dose = DFR * Tc * hours of daily exposure (8 hrs) * conversion factors ( μ g to mg) / 8 0 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 toxici ty (NOAEL 10 mg/kg/day). Risks were calculated using the MOE approach, which is a ratio of the exposure to the toxicological PoD. O ccupational 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
Coefficients 1

cm 2 /hr Application

Rate 1
lb inert/Acre DFR

Levels 2 μg/cm 2 Short

term Dose 3 mg inert/kg /day MOE 4

Insecticide Short

- term Tall Field Row
Low: scouting, weeding immature/low foliage plants 100

0. 3 5 lb ienrt/A 0.132 0.0 06 2 39 00

Medium: scouting, weeding more mature/foliaged plants 400 0. 0247 96 0

High: scouting, irrigation, weeding mature/full foliage plants 1000 0. 0617 39 0

Insecticide Short

- term Turf
Low: Mowing 500 0. 3 5 lb inert/A 0.687 0. 008 31 00 High: Transplanting, handweeding 6800 0.10 5 230
Insecticide Short

- term Vinetrellis
Low: Hedging, irrigation, scouting, hand weeding, training/tying
blueberries 500

0.24 5 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 11033

VII. C UMULATIVE EXP OSURE

Cumulative effects from su bstances 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 particula r 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 informatio n 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. E NVIRONMENTAL 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 Lo w

- 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, R D estimates risks to population subgroups from pesticide exposures that are based on patt erns 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,

spec ialized 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 b ystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups

.

IX. E NVIRONMENTAL FATE CONSIDERATIONS34

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 estim ated 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 trans

isomers, 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 th at 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%, wat er 50%, soil 50%, sediment 0.02%.

X. E COTOXICITY

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 ac ute 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 gaird neri ) and bluegill ( Lepomis
macrochirus ) studies. These reported 96 hour LC 50 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 CaCO 3 ) with temperatures of 12oC (trout) and 22oC ( bluegill).

Other published scientific studies ( Klimisch code 2B or 2C ) were a 96 hour LC 50 of 230 mg/liter for the mosquitofish ( Gambusia affinis ) ( Wallen et al 1957 ), a 48 hour LC 50 of 115 mg/liter for Golden orfe ( Leuciscus idus melanotuse ) ( Knie et al. 1983 ), and a 48
hour LC 50 of 138 mg/liter for bluegill ( Lepomis macrochirus ) ( Turnbull et al. 1954 ).

Aquatic Invertebrate Toxicity35

Acute toxicity to the freshwater invertebrate Daphnia magna was reported as 48 hour
EC 50 of 330 mg/liter ( ABC Labora tories, 1982c ). No effects were ob served at 180 mg/liter or lower concentrations. Test material concentrations were not measured.
Dil ution water was well water with total hardness of 255 mg/liter as CaCO 3 . Test temperature w as 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 EC 50 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 fa ctor 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 EC 50 can be est imated as > 130 mg/liter. Algae were grown and tested using AAP (Algal assay procedure m edium) at 26oC under continuous illumination. Microscopic observations showed no abnormal cells in any treatment. Test stock solution was adjusted
at test initiation fr om pH 2.9 to pH 7.5 using sodium hydroxide.

XI. R ISK 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 manufactu re 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 is36

then hydroxylated to malic a cid, which participates in the K rebs 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 LD 50 and a dermal LD 50

. The two studies used were the oral rabbit LD 50 of 875 mg/kg and the dermal rabbit LD 50 of 2620 mg/kg maleic anhydride. The resu lting 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 hy perplastic 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 fo r 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. D ermal 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 sho w 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 DEEM

FCID TM , Version 3.16. The chronic population

- adjusted dose (cPAD) 0.1 mg/kg/day.

Based on analyses of estimated dietary risks for the gene ral 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 i s 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 anhyd ride 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

- sp ecies sensitivity.

Outdoor residential applicator exposures were calculated using t hree exposure scenarios, low pressure handwand, hose end sprayer and trigger sprayer were assessed for each pesticide type, herbicide, insecticide and fungicide in both s hort

- and intermediate

- term scenarios. The37

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 appli cator 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. Th e 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, thi s 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 short

and intermediate

- term exposures 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.

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. Usin g 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 co mbines 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.

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 Ag ency 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 aggregat ed 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
residenti al 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 aggre gate MOE of 1 19 for38

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

- mou th ). 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 gr eater 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 estim ated 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 fat e 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 ), fres hwater 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 Minorit y 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 establishmen t of an exemption from the requirement of a tolerance
under 40 CFR 180.92 0 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

ABC Laboratories, Inc. (1982a) Acute Toxicity of Maleic Anhydride to Rainbow Trout. 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
studi es 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. (19 82) 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 CII T, 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. (197 9b) 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) Salmonell a 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 Am es. 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. D

1248. Submitted to USEPA by Dow Chemica l 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. D

001249. 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 Mons anto 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 vi er 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 Ass essment Profile (SIAP) for Maleic Anhydride and Maleic Acid. Summary of SIDS Submission to the Organization for Economic Cooperation and41

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 Anhydri de 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 Anh ydride 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 Stud y No. 13761.6103

Springborn Smithers Laboratories (2002b) Maleic Anhydride

– Determination of the n

Octanol/Water Coefficient. Conducted for the American Chemistry Council Maleic Anhydride Panel. Unpublished Report, Springborn Smithers Study No. 13761.61 08

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.

S pringborn 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.

Turnbull, H., DeMann, J. G., and Weston, R. F. (1954) Toxicity of various refinery materials to fresh water fish. Industr. Engineer. Chem. 46: 324

- 333.

U.S. Food and Drug Administration (FDA). 2006. The List of “Indirect” Additives Used in Food
Contact Substances Database. http://www.cfsan.fda/gov/~dms/eafus.html

.42

U.S. Environmental Protection Agency (EPA). 2006a Integrated Risk Information System (IRIS). http://www.epa.gov/iris

.

U.S. Environmental Protection Agency (EPA). 2006b Reassessment of the One Exemption from the Requirement of a Tolerance for Maleic Anhydride (CAS # 108

- 31

- 6) and Maleic Acid (CAS# 110

- 16

- 7).

Wallen , I. E., Greer, W. C., and Lasater, R. (1957) Toxicity to Gambusia affinis of certain pure chemicals in turbid waters. Sewage Industr. Wastes 29: 695

- 711.43

APPENDIX

US EPA Ver. 3.16, 03

- 08

- d

DEEM

- F CID 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

Assessmen t 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 0.011 222 11.2%
Male 20+ 0.010839 10.8% Female 20+/NP 0.011709 11.7%

Seniors 55+ 0.011677 11.7%

All Infan ts 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%

Adu lts 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 toler ance (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 hav e either post

- harv est 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 A pple 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

- (Merca ptomethyl) 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

- meth yl 180.132 Apple 7 Thiram 180.476 Apple 0.5 Triflumizole 180.116 Apple 7 Ziram