


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

EPA Registration Division contact: Kerry Leifer 202-566-2812


TEMPLATE:

Valent BioSciences LLC

IN-11559

	EPA has received a pesticide petition IN-11559 from Valent BioSciences LLC, 1910 Innovation Way, Suite 100, Libertyville, Il, 60048 requesting, 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 180.920 to establish an exemption from the requirement of a tolerance for malic acid (CAS Reg. No. 6915-15-7) in or on the raw agricultural commodities.  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. Malic acid is an organic acid naturally found in plants, especially in apples and other fruits and vegetables.  In plants, malic acid (MA) is metabolized in mitochondria, acts as a common reserve anion in the plant vacuole, and is a counter ion for K and Ca cations, especially in nitrate-dependent plants

	2. Analytical method. As an exemption from tolerance is being requested, an analytical method to look for malic acid in food crops is not considered necessary.  Nevertheless, there are multiple analytical methods available in the literature, which have been used to measure malic acid content of fruits and other crops.
Malic Acid has been detected and quantified, in general foods and in fruits and fruit derivatives using fluorometry, GC, gas-liquid chromatography, thin layer chromatography (TLC), paper chromatography, polarimetry, manometry, and ion exchange plus ultraviolet (UV), and in synthetic mixtures of food acids using TLC, thin layer electrophoresis plus chromatography, and fluorometry.

	3. Magnitude of residues. [An exemption from tolerance is being requested as natural compound found in fruits and vegetables and already permitted in foods at levels higher than would be found on a crop by the use of malic acid as an inert. ]


B. Toxicological Profile

 Acute toxicity.  
Mouse
LD50
oral
1600 mg/kg 
Rabbit
LD50
oral
3000 mg/kg
         
         Malic acid and its salts are considered as strongly irritant to the skin and mucosa.
         Malic acid in its pure form can cause serious eye damage.
         

	2. Genotoxicty. [Malic Acid was not mutagenic across a range of genotoxicity tests.  An Ames test was performed to determine the mutagenic potential of Malic Acid in phosphate buffer, ·10.0 mg/plate, using S. typhimurium strains TA92, TA1535, TA100, TA1537, TA94, and TA98 with metabolic activation (Ishidate et al. 1984).
Testing was done in duplicate. Malic Acid was not mutagenic.  A chromosomal aberration test was performed without metabolic activation using a Chinese hamster . broblast cell line to determine the mutagenic potential of ·1.0 mg/ml Malic Acid
in physiological saline (Ishidate et al. 1984). The incidence of polyploid cells and cells with structural chromosomal aberrations was 0% and 1%, respectively, after 48 hours. Malic Acid was not mutagenic.]

	3. Reproductive and developmental toxicity. [Malic acid did not cause reproductive toxicity in mice, rats, or rabbits.  In a tow generation reproductive study, the second generation, receiving malic acid their entire development no "meaningful differences" between test and control animals in the number and placement of implantation and resorption sites or in the number, weight, or length of live neonates, and none of the neonates died. The skeletal development of the neonates was similar between test and control animals. Slight differences in developmental indices were "considered to be within the range of normal variations in fetal development. No trends toward lesser
or greater skeletal development were observed."

	4. Subchronic toxicity. [The studies conducted have centered on developmental and reproductive effects and on chronic toxicity.  None of these studies have produced toxicological endpoints of concern]

	5. Chronic toxicity. [In a chronic oral study, feeding malic acid to rats resulted only in weight gain changes and changes in feed consumption.  Groups of 30 male and 30 female Charles River rats were fed 500, 5000, or 50,000 ppm (0.05%, 0.5%, and 5.0%, respectively).   Malic Acid for 104 weeks, and a control group of 60 male
and 60 female rats was given untreated feed.  Significant changes were not observed in
hematological, blood, or urine parameters. Significant lesions were not found at gross and microscopic examination]

	6. Animal metabolism. [Malic acid is involved in the Krebs cycle and other metabolic proceses. The Krebs cycle is a process the body uses to make energy]
The amount of radioactivity recovered after oral and IP administration of DL-Malic Acid was 3.1% and 8.8% in the urine and 0.6% and 0.3% in the feces, respectively, and the amount recovered after oral and IP administration of L-Malic Acid was 3.2% and 3.1% in the urine and 1.4% and 1.4% in the feces respectively.  Most of the radioactivity was
excreted as carbon dioxide; after 24 hours, 91.6% and 83.4% of orally and intraperitoneally administered DL-Malic Acid, respectively, and 88.0% and 86.6% of orally and intraperitoneally administered L-Malic Acid, respectively, was found in expired air.

	7. Metabolite toxicology. [Malic acid has been consumed in apples and other fruits and vegetablesfor millenia, and malic acid is part of the body's inherent energy metabolism, thus the metabolites can not be considered toxic.

	8. Endocrine disruption. [No indications of an endocrine effect have been seen in the developmental of reproductive studies, nor the chronic exposure studies.]

C. Aggregate Exposure

	1. Dietary exposure. A healthy diet in fruits and vegetables will provide a natural intake of malic acid.  The average content of L-Malic acid in apple juice is said to be between 0.3 and 0.6 g/100g.  Watermelon also contains a high amount of malic acid, at about 105 mg/g, Other fruit sources of malic acid include bananas, apricots, blackberries, cherries, lychees, peaches, pears and nectarines.  It is found in vegetables such as carrots and broccoli.

	i. Food.   Malic acid is permitted by FDA when used as a flavor enhancer, flavoring agent and adjuvant as defined 21CFR,
Malic acid is used in food, except baby food, at levels not to exceed good manufacturing practice in accordance with § 184.1(b)(1). Current good manufacturing practice results in a maximum level, as served, of 3.4 percent for nonalcoholic beverages; 3.0 percent for chewing gum; 0.8 percent for gelatins, puddings, and fillings; 6.9 percent for hard candy; 2.6 percent for jams and jellies; 3.5 percent for processed fruits and fruit juices; 3.0 percent for soft candy; and 0.7 percent for all other food categories

	ii. Drinking water. [Malic acid when used as an inert in crop production should not make its way into drinking water due to its rapid biodegradation, but due to its lack of toxicological end points of concern, risk should be minimal.]

	2. Non-dietary exposure. [Malic acid should not present non-occupational, non-dietary exposure (e.g., textiles (clothing and diapers), carpets, swimming pools, and hard surface disinfection on walls, floors, tables).]

D. Cumulative Effects

	[No cumulative negative effects are expected from the use of Malic Acid as an inert on crops due to its biodegrability and the metabolism of malic acid by plants and microbes.  Thus this use is not expected to contribute significantly to the malic acid intake of the populace. ]  

E. Safety Determination

	1. U.S. population. [Based on the lack of threshold effects, and that there are no  toxicological endpoints of concern, conducting a qualitative assessment of malic acid there is not a concern. for the U.S. population, including infants and children]

	2. Infants and children. [Based on the lack of threshold effects, and that there are no  toxicological endpoints of concern, conducting a qualitative assessment of malic acid there is not a concern. for the U.S. population, including infants and children]

F. International Tolerances

	[No Codex or International tolerances are available, but Malic acid is permitted added to foods and feeds internationally.]




