


EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: PV Shah, 703-308-1846

INSTRUCTIONS:  Please utilize this outline in preparing the pesticide petition.  In cases where the outline element does not apply, please insert "NA-Remove" and maintain the outline. Please do not change the margins, font, or format in your pesticide petition. Simply replace the instructions that appear in green, i.e., "[insert company name]," with the information specific to your action.

TEMPLATE:

Cheminova A/S

[IN-10771]

	EPA has received a pesticide petition (IN-10771) from Cheminova A/S, EPA Company Number 4787, 1600 Wilson Boulevard, Suite 700, Arlington, VA  22209 proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180. to amend an exemption from the requirement of a tolerance for Maleic anhydride (CAS Reg. No. 108-31-6) and maleic acid (CAS Reg. No. 110-16-7) when used as an inert ingredient (stabilizer) in pesticide formulations applied to growing crops, at a maximum of 5% in the pesticide formulation.  EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of  FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

	1. Plant metabolism. Not applicable to this petition

	2. Analytical method. Not applicable to this petition

	3. Magnitude of residues. Not applicable to this petition




B. Toxicological Profile

Maleic anhydride and maleic acid are currently approved by EPA for use as inert ingredients in pesticide formulations applied to growing crops (specifically apples with a 21-day pre-harvest interval) as described at 40 CFR §180.920.  Cheminova is specifically interested in amending the tolerance exemption for maleic anhydride.  However, because maleic anhydride and maleic acid are listed together in the current tolerance exemption in 40 CFR §180.920 and because they were reassessed together by EPA, this petition proposes a revision of the tolerance exemption covering maleic anhydride and maleic acid.  These two compounds reference a majority of the same toxicology data, as described in the Agency's tolerance reassessment, and the toxicology endpoints are the same.  Further, maleic anhydride rapidly hydrolyzes to maleic acid and both compounds are readily biodegradable. Thus, maleic anhydride and maleic acid are therefore biologically equivalent.  Accordingly, bridging the database of toxicological and environmental data for maleic anhydride and maleic acid is a scientifically sound approach.  Since the maleic anhydride is the use of interest, it is the focus of this petition. 

	1. Acute toxicity.  Based on available toxicological information, maleic anhydride exhibits relatively low acute toxicity via oral and dermal routes of exposure.  Maleic anhydride has been reported to be severely irritating to the skin and eyes of rabbits. It is dermally sensitizing to guinea pigs, and is a potential respiratory sensitizer to rats. 

	2. Genotoxicty. Limited in vitro and in vivo genotoxcity tests conducted with maleic anhydride are negative.  On the basis of all of the data on genotoxicity, a mutagenic effect is not assumed.

	3. Reproductive and developmental toxicity. No treatment-related reproductive or developmental effects were reported in published animal studies following oral exposure to maleic anhydride.

Male and female rats were dosed with maleic anhydride by gavage at 0, 20, 55 or 150 mg/kg/day in a multi-generation reproductive study.  No adverse effects on fertility were noted at doses up to 55 mg/kg/day administered over two generations.  In the parental group, mortality, body weight changes, and respiratory irritation were seen at the highest dose level, 150 mg/kg/day.  In addition, histopathological effects were observed in the kidney and bladder of the first generation parental animals in all treated groups.  No adverse effects on litter size and on pup survival were noted at doses up to 150 mg/kg/day.  The LOAEL for parental effects was 20 mg/kg/day and the NOAEL for reproductive effects was 55 mg/kg/day, the highest dose tested due to parental death at 150 mg/kg/day.

No developmental toxicity was observed when pregnant CD rats were treated with maleic anhydride via gavage at 0, 30, 90, and 140 mg/kg/day from day 6 to day 15 of gestation.  There were no reported treatment-related effects upon examination of the fetuses for external abnormalities, soft tissue abnormalities and skeletal abnormalities.  No increases in fetal malformations were noted, and the variations detected were similar in the control and treated groups.  The NOAEL for maternal and developmental toxicity was determined to be 140 mg/kg/day.

The effects seen in these studies are likely representative of maleic acid toxicity since maleic anhydride is rapidly hydrolyzed to maleic acid in the body, particularly via oral exposure  

	4. Subchronic toxicity. Repeat dose 90-day feeding studies have been conducted in rats and dogs for maleic anhydride.  Additionally, repeat dose inhalation studies were conducted in several species.

In a 90-day oral feeding study, rats were administered maleic anhydride at dose levels of 0, 100, 250, or 600 mg/kg/day.  Effects on the kidney occurred at relatively high doses (>= 100 mg/kg/day) and were more severe in males than in females.  The effects appear to be largely in the tubular cells, with some effects occurring in the glomeruli.  Since maleic anhydride rapidly hydrolyzes to maleic acid under aqueous conditions, the kidney effects are likely due to maleic acid.  Maleic acid is also known to cause kidney damage with the target site being tubular cells.  The LOAEL for this study is 100 mg/kg/day.  In a separate 90-day oral study discussed in the same report, rats were administered doses of 0, 20, and 40 mg/kg/day of maleic anhydride.  The NOAEL was determined to be 40 mg/kg/day based on no treatment related effects.  

In a 183-day study, male rats were fed 0, 250, or 600 mg/kg/day maleic anhydride.  The LOAEL was 250 mg/kg/day, based on effects in the liver and kidneys.

No adverse effects related to maleic anhydride were observed in a dietary feeding study in dogs dosed at 0, 20, 40, or 60 mg/kg 7 days a week, for 90 days. In the high-dose group, there was a decrease in food intake for the first few weeks.  The LOAEL was determined to be 60 mg/kg/day for hematological effects, and the NOAEL was 40 mg/kg/day.

In a repeat dose inhalation study, rats were exposed to maleic anhydride at concentrations of 0, 12, 32, or 86 mg/m[3] (0, 3, 8, or 21 ppm) for 6 hr/day for 4 weeks.  Evidence of nasal, trachea and lung irritation was present at all exposure levels.  Effects of maleic anhydride were concentration related and included epithelial hyperplasia and the presence of inflammatory exudates in the nasal turbinates and trachea, and epithelia hyperplasia, squamous metaplasia, and intra-alveolar hemorrhage in the lung.  Increased incidence of hemorrhagic lung foci were observed in the 32 and 86 mg/m[3] exposed group.  The LOAEL was 12 mg/m[3] (3 ppm).

Respiratory tract and eye irritation were observed in rats, hamsters and monkeys when exposed to maleic anhydride at concentrations of 0, 1.1, 3.3, and 9.8 mg/m[3] (0, 0.3, 0.8, or 2.4 ppm) for 6 hr/day, 5 days a week for 6 months in a repeated inhalation study.  Respiratory tract and eye irritation were observed in rats and hamsters exposed to 3.3 and 9.8 mg/m[3], and in monkeys at 9.8 mg/m[3].  Also observed were body weight reductions in male rats from the high-exposure group (9.8 mg/m[3]). In both male rats and hamsters, hyperplastic and metaplastic changes of the nasal tissues, ranging in severity from trace to mild, were present and were observed in rats at all exposure levels and in hamsters at the mid- and high-exposure levels; these changes are considered a sign of irritation and were judged reversible.  The NOAEL for rats was determined to be 3.3 mg/m[3] (0.8 ppm).

	5. Chronic toxicity.  In a two-year rat oral chronic study, rats were fed maleic anhydride at the dose levels of 0, 10, 32, or 100 mg/kg/day.  Effects at the LOAEL included a slight to marginal decrease in body weight in male rats at 32 mg/kg/day and 100 mg/kg/day.  Female rats at those doses showed a marginal decrease in body weight.  There were no other adverse effects indicated.  The NOAEL was 10 mg/kg/day in males and females.

Maleic anhydride is not classifiable as a human carcinogen.

	6. Animal metabolism. There is limited information regarding the metabolism and pharmacokinetics of maleic anhydride.  Under aqueous conditions, maleic anhydride is hydrolyzed to maleic acid.  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.  Maleic anhydride has the potential to form haptens by acrylating with amino acids and resulting in an immunological response (dermal and respiratory sensitization).

In a metabolism study, dogs were fed 60 mg/kg/day maleic anhydride for 990 days.  Using a one compartment model, uptake rate and elimination rate constants were calculated as 3.49 x 10[-3] per day and 8.32 x 10[-2] per day, respectively.  Based on this model, "99% of steady state was reached by day 55 of the study."

	7. Metabolite toxicology. There are no metabolites of toxicological concern.

	8. Endocrine disruption. EPA has not reported having any available information to suggest that maleic anhydride would have any endocrine effects.  When the appropriate screening and/or testing protocols under the EDSP have been developed, maleic anhydride and maleic acid may be subject to additional screening and/or testing to better characterize effects related to endocrine disruption.  This does not impact the current regulatory status of maleic anhydride.

C. Aggregate Exposure

	1. Dietary exposure.  For maleic anhydride, only chronic exposures are of interest because there is no relevant acute toxicity endpoint.  The maximum concentration of maleic anhydride in pesticide formulations will be 5%.  Thus, the inert ingredient default screening-level chronic dietary estimates can be adjusted to reflect this limited concentration in formulations.  Estimated chronic dietary exposures range from 0.015 mg/kg/d for youth 13-19 years old to 0.073 mg/kg/d for children aged 1-2 years old, the most highly exposed subpopulation.  When expressed as a percent of the cPAD, these exposures range from 14.9% to 73.3% of the cPAD.  Dietary exposures below the cPAD are not of concern.

The results of the dietary risk assessment demonstrate that maleic anhydride dietary exposures will be less than the chronic reference dose for all subpopulations when it is present at no more than 5% in pesticide formulations.  Therefore, this dietary assessment supports a safety finding for a tolerance exemption for maleic anhydride in pesticide formulation at a concentration of no greater than 5%.

	2. Non-dietary exposure. Based on the proposed 40 CFR §180.920 uses cited herein, residential exposure of maleic anhydride is not expected to occur.   

D. Cumulative Effects. EPA has not made a common mechanism of toxicity finding for maleic anhydride or maleic acid and neither appears to produce a toxic metabolite that is produced by other substances.  Therefore, it should be assumed that maleic anhydride and maleic do not have a common mechanism of toxicity with other substances.

E. Safety Determination

	1. U.S. population. As part of the FQPA tolerance reassessment process, the Agency stated that a qualitative dietary risk assessment was appropriate based on the "lack of human health concerns associated with the low levels of exposure to these chemicals when used as inert ingredients in pesticide formulations."  Since Cheminova is requesting to amend the tolerance exemption to include all food use applications as described in 40 CFR §180.920, and there may therefore be broader use of these inert ingredients, a quantitative dietary risk assessment incorporating the limitation of 5% in pesticide formulations has been conducted.

Based on this quantitative dietary risk assessment using the toxicological endpoint of 10 mg/kg/day and an uncertainty factor of 100, the total exposure estimates for the U.S. population are below 20.8% of the cPAD of 0.1 mg/kg/day.  For the most highly exposed population subgroup, children 1-2 years, the exposure estimate is 73.3% of the cPAD.  These exposure estimates demonstrate that there is reasonable certainty of no harm to all population subgroups as a result of dietary exposure to maleic anhydride when used according to pesticide applications consistent with 40 CFR §180.920.

	2. Infants and children. The two-generation reproductive study in rats resulted in no adverse effects on fertility up to the NOAEL of 55 mg/kg/day.  There were no adverse effects on litter size and pup survival up to 150 mg/kg/day.  In a rat developmental study using maleic anhydride, there were no treatment related effects noted in the examination of the fetuses for external abnormalities and no fetal malformations were noted.  Based on these available reproductive and developmental toxicity studies conducted with maleic anhydride, there is no concern for increased sensitivity to infants and children to this compound when used as an inert ingredient in pesticide formulations.  

Therefore, an additional FQPA safety factor is not required for the risk assessment.

F. International Tolerances
Currently there are no known Codex MRLs established for maleic anhydride.
