DATE: UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

8 JANUARY 2014 OFF I CE OF CH E M I CAL SAFETY AND PO LLUT ION PREVENTION

MEMORANDUM

SUBJECT: D -mannose; Human Health Risk Assessment and Ecolog i cal Effects Assessment to Support a Proposed Exemption from the R equirement of a Tole r ance When Used as
an I nert Ing r edient in Pesticide Formu l ations.

FROM:

TO: PC CODE: 700023; CASRN: 3 458- 28-4;

. Peti t ion No.: 1 E79 03;**gulatory** Action: 40 CF R 180 .920

Mark I. Dow , Ph.D. 

## vJfl 

# &flJ

Senior Biologist 

## f /}Jt Inert Ingredient Assessment Branch (IIA B ) Registration Division (7505P) A A

_ 11 

# Jr.-.

P.V. Shah
, Ph.D.

## ~-'6\J'-Y Chief, Inert Ingredient Assessment Branch (IIAB) Regi strat i on Division (7505P)

EXECUTIVE SUMMARY

This is the Deci sion Document for D-mann ose ; Pestic ide Petition 01E7903 ; CASRN 3458

- 28 -4 ; PC Code: 700023. The ISK BIOSCIENCES Corpo r ation, (7470 Auburn Road, Suite A, Concord, OH 44077) a who ll y owned subsidiary of Ishihara Sangyo Kaisha, L td., has submitted

a petition requesting an exempt ion from the r equirements of a tolerance for the compound Dmanno se (CASRN 3458-28-4; PC Co d e: 70002 3)

. Specifically, the requ est i s to use D-manno se
as an inert ingredient which acts as a sequestrant/binder/fi ll er in pes t i c id e formulations applied pre-harvest to all raw agricultural commodities under 40 CFR § 180.9 20.

D-Mannose is a simple
, six carbon sugar (molecular formula C6-Hl2-06) whic h occurs naturally in mammalian metabolic systems.2 The metabolism of D

- Mannose is well documented. D

- Mannose is involved in an extensive series of metabolic transformations being ultimately incorporated into glycoproteins and glycolipids or is formed into the sugar fucose which is then incorporated in gly coproteins. The glycoproteins and glycolipids are essential to the maintenance of cellular integrity and to cell generation.
Mannose occurs as the free sugar in peaches, apples and oranges. D

- Mannose has been extensively evaluated for clinical use in the treatment of RUTIs (recurrent urinary tract infections). It is approved as a dietary supplement and as such marketed widely.
In addition to oral exposure from ingestion via natural occurrence in some fruits and vegetables, individuals may experienc e oral exposure and dermal exposure to residues on treated crop sites. Since no toxicological endpoint of concern (oral, dermal or inhalation) has been identified and since D

- Mannose is known to be essential to mammalian metabolic systems, it is not neces sary to quantify exposures. No adverse effects have been identified which are attributable to exposures to D

- Mannose. No adverse effects have been identified in the public literature.
The toxicity database is considered complete. There is no evidence of toxicity found in health and toxicological internet databases. On the contrary, there is ample evidence that D

- mannose is integral to mammalian metabolic systems in the formation of glycoproteins. There is no

e vidence of neu ro toxicity as a result of exposure to D

- mannose

. There is no evidence of increased susceptibility to infants or children. There are no residual uncertainties identified in the exposure databases. Since no toxicological endpoints can be identified, a quantitative risk assessment is not necessary.

D

- mannose occurs naturally in a number of agricultural food items. It occurs in all mammalian systems evaluated. The Agency does not expect adverse ecological or environmental effects as a result of the proposed agricultural use of D

- mannose in pesticide products.
In view of the plethora of documentation regarding the metabolic pathways of D

- mannose ; the biological significance of its contribution to glycoprotein and glycolipid synthes e s in mammalian systems; its natural occurrence in such fruits as peaches, apples and oranges; its ‘clinical’ use to treat urinary tract infections and possible periodontal conditions, its widespread marketing and use as a dietary supplement and upon the la ck of adverse risk or toxicological information, the Agency approves of the use of D

- mannose (CASRN 3458

- 28

- 4; PC Code: 700023) as an inert ingredient which serves as a sequestrant/binder/filler in pesticide formulations applied pre

harvest to all raw agr icultural commodities. The approval is for exemption from the requirements of a tolerance under 40 CFR § 180.920 (preharvest application to raw agricultural commodities).

I

. BACKGROUND

This is the Decision Document for D

- mannose ; Pesticide Petition 01E7903; CASRN 3458

- 28

- 4; PC Code: 700023. The ISK BIOSCIENCES Corporation, (7470 Auburn Road, Suite A, Concord, OH 44077) a wholly owned subsidiary of Ishihara Sangyo Kaisha, Ltd., has submitted a petition requesting an exemption from the requirements o f a tolerance for the compound D

-3 mannose (CASRN 3458

- 28

- 4; PC Code: 700023). Specifically, the request is to use D

- mannose as an inert ingredient which acts as a sequestrant/binder/filler in pesticide formulations applied pre

- harvest to all raw agricultu ral commodities under 40 CFR § 180.920

.
II . Inert Ingredient Profile

A. Summary of Uses The request is to use D

- mannose as a sequestrant , binder or filler in pesticide formulations applied pre

- harvest to all raw agricultural commodities. In mammalian systems, the primary source of D

- mannose is the sugar glucose. D

- mannose undergoes extensive metabolic transformation by being incorporated into glycop roteins and glycolipids. Or, it is formed into the sugar f r uc t ose that is then incorporated into glycoproteins. D

- mannose occurs as the free sugar in peaches, apples and oranges. It is absorbed from the gastrointestinal tract of rats at only 12 % the ra te of glucose.

B. Physical Chemical Properties
The chemical structure and p hysical/chemical properties of D

- mannose follow: (adopted from MSDS

– Sciencelab.com, Inc. 11/01/2010).

Physical state/appearance : Solid (solid crystalline powder) Odor: Odorless Taste: Sweet Molecular Weight: 180.16 g/mole Color: Colorless to light yellow pH (1% soln/water) not available Boiling pt. not available Melting pt. Decomposes. (132o C or 169.6o F). Critical temperature: not available Specific gravity: 1.539 (Water = 1) Vapor pressure: not applicable Vapor density: not available Solubility: soluble in cold water (MSDS

– Sciencelab.com, Inc. 11/01/2010 O

OH HO OH

HO

OH4 III

. Hazard ASSESSMENT

A. Summary of Toxic ity Data

.
D

- mannose is a naturally occurring compound and is a normal constituent of the human diet. D

mannose is a ubiquitous component of mammalian sera. Searches of the internet reveal not data or information indicating adverse effects from exposure to this chemical.

B. Toxicity Profile
Acute Toxicity No information or evidence has been found to suggest that there is any acute toxicity
, subchronic toxicity, chronic toxicity, neurotoxicity, mutagenicity, developmental or reproductive toxicity or carcinogenicity from exposure to D

- mannose

. Gheyas et al. (1996) studied the dietary fiber composition of ‘Starkspur Supreme Delicious’ apple fruit. They discovered differences in the relative amount of monosaccharide residues in apple fiber depending upon root stock. The monosacharides they found were rhamnose, f r uc t ose, arabinose, xylose, D

- mannose , galactose and glucose. This paper helps document the “natural” existence of D

- mannose from dietary sources.

Metabolism and Pharmacokinetics

D

- Mannose is a simple, six carbon sugar (molecular formula C6

- H12

- O6) which occurs naturally in mammalian metabolic systems. Alton et al. (1997) found D

- Mannose to be essential to the metabolism of 33 species of animals including primates, marsupials, rod ents, lagomorphs, canine carnivores (bears, foxes, dogs), feline carnivores, artiodactyls (including cows and Bactrian camels), perissodactyls (rhino) and proboscids (elephants).
In addition to the study by Alton et al., Herman (1971) provides a monographic review of the metabolism of D

- Mannose. The metabolism of D

- Mannose is extremely well documented. D

Mannose is involved in an extensive series of metabolic transformations bein g ultimately incorporated into glycoproteins and glycolipids or is formed into the sugar fucose which is then incorporated in glycoproteins. The glycoproteins and glycolipids are essential to the maintenance of cellular integrity and to cell generation.
Bartlett (1959 and 1968) has shown that human red blood cells contain an unusually high concentration of mannose phosphorylation products. Human erythrocytes phosphorylate mannose using an enzyme indistinguishable from hexokinase. D

- mannose is found i n the tissues of a number of organs. Research suggests that mammalian systems use mannose transporters to deliver mannose to the liver and other organs for glycoprotein biosynthesis (Alton et al. 1997).5 Mannose is shown to occur in the heart, spleen, lung, kidney, brain, muscle, liver and liver plasma and intestine. Human amniotic fluid has been shown to contain mannose in concentrations comparable to the concentration that occurs in the blood.
Mannose occurs as the free sugar in peaches, apples and oranges. As such it is absorbed from the gastrointestinal (GI) tract of rats at about 12 % of the absorption rate of glucose. It is thought that mannose may be liberated from dietary glycoproteins and glycolipids by the action of mannosidase in the GI t ract. Gheyas et al. (1996) studied the dietary fiber composition of ‘Starkspur Supreme Delicious’ apple fruit. They discovered differences in the relative amount of monosaccharide residues in apple fiber depending upon root stock. The monosacharides the y found were rhamnose, f r uc t ose, arabinose, xylose, D

- mannose , galactose and glucose. This paper helps document the “natural” existence of D

- mannose from dietary sources.

D

- Mannose has been extensively evaluated for clinical use in the treatment of RU TIs (recurrent urinary tract infections). It is approved as a dietary supplement and as such marketed widely.
Some metabolic mannose is derived from glucose. Glucose intolerance may occur in hypersensitive individuals. Very high doses of glucose may cause diarrhea. No implication of toxicity to D

- mannose has been found.

“ D

- mannose and fucose are found in a great variety of glycoproteins. The D

- mannose and fucose content of glycoproteins is reviewed by Eylar (1965).”
Alton et al. (1987) present a comprehensive discussion of the direct utilization of D

- mannose for glycoprotein biosynthesis. I t was believed that cellular D

- mannose was derived entirely from glucose. The results of the Alton et al. study indicate that mammals use D

- mannose transporters to deliver D

- mannose from the blood to the liver and other organs for glycoprotein synthesis. Alton et al. say “additionally and contrary to expectations, most of the D

- mannose for glycoprotein biosynthesis in cultured hepatoma cells is deri ved from D

- mannose , not glucose. Extracellular D

- mannose may also make a significant contribution to glycoprotein biosynthesis in the intact organism.” D

- mannose is integral to mammalian homeostasis.
According to the Small Molecule Pathway Database (S MPDB), mannose is not well metabolized in humans and it does not significantly enter most carbohydrate metabolism pathways when taken orally. Indeed it appears that 90% of mannose ingested is excreted unconverted into the urine within 30

- 60 minutes, with 9 9% of the remainder being excreted within the following 8 hours. On the other hand, mannose is present in numerous gl y coconjugates including N

- linked glycosylated proteins. What little mannose that is metabolized appears to be phosphorylated and either con verted to GDP mannose and sent on to N

- glycan biosynthesis or it is isomerized by

mannose

- 6

- phosphate isomerase i nto beta

- fructose

- 6

- phosphate,w hich then can be directed into the fructose catabolic pathway and ultimately enter the glycolysis pathway to produce energy in the form of ATP for the organism

.6 C . Toxicity Endpoint Selection

T here are no data or other information which indicate any signs of toxicity in normally functioning mammalian systems as a result of the presence of D

- mann ose. In addition, many studies described the pharmacological benefits from treatment with D

- mannose

. A toxicological endpoint of concern has not been identified. A quantitative risk assessment is not necessary and was not performed.

IV. FQPA Safety Factor considerations

1. In general . Section 408(b)(2)(c) of FFDCA provides that EPA shall apply an additional tenfold (10X) margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the database on toxicity and exposure unless EPA determines based on reliable data that a different margin of safety will be safe for infants and children. This additional margin of safety is commonly referred to as the FQPA safety factor (SF). In applying this provision, EPA either retains the default value of 10X, or uses a different additional safety factor when reliable data available to EPA support the choice of a different factor.
Given the lack of concern for hazard posed by D

- mannose , EPA concludes that there are no dietary or aggregate dietary/non

- dietary risks of concern as a result of exposure to D

- mannose in food and water or from residential exposure. Taking into consideration of all ava ilable information on acetone, E PA concludes that there is a reasonable certainty that no harm will result to the general population, or to infants and children from aggregate exposure to acetone residues. Based on the weigh t of evidence presented above, EPA concluded that the FQPA factor should be removed.

V

. Exposure Since no toxicological endpoints of concern have been identified, it is not necessary to conduct dietary, dermal or inhalation exposure assessments.

Cancer exposure . There is no evidence that D

- mannose is carcinogenic. Therefore, a cancer dietary exposure assessment is not necessary to assess cancer risk.
Analytical Methodology
Since this request is for an exemption from the requirement of a tolerance, an analytical method for enforcement purposes is no t required to support this action.
Residential (Non

- Occupational) Exposure

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). “Residential” use patterns were n ot7 identified in the Registrant’s proposed use of D

- mannose . Therefore, “residential” exposure is not expected. Further, there are no toxicological endpoints of concern identified with which to conduct an exposure and risk assessment. The proposed use d oes not exceed the Agency’s levels of concern.

VI. Aggregate Risk
There is no evidence to suggest concern for acute exposures, short

- term exposures or intermediate

- term exposures. No toxicological endpoint(s) have been identified therefore risk assessments are not necessary and have not been conducted.

.
VII. Cumulative Exposure
Cumulative effects from substances with a common mechanism of toxicity . Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider “available information” c oncerning the cumulative effects of a particular pesticide's residues and “other substances that have a common mechanism of toxicity.”

EPA has not found D

- mannose to share a common mechanism of toxicity with any other substances, and D

- mannose does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has assumed that the D

mannose does not have a common mechanism of toxicity with other substances. For information regarding E PA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see EPA's website at http://www.epa.gov/pesticides/cumulative

.
VIII

. Environmental Fate
In support of the petition, the Registrant characterized the potential environmental fate and effects by the use of the predictive model EPISuite ®

. Based on the EPI Suite calculations of physical properties for D

- mannose, it is not expected to be of great concern in the en vironment. The log Kow of

- 2.43 and water solubility of 7.13x10 5 mg/L suggest that D

- mannose is high soluble in water. Also based on the vapor pressure of 1.62x10

- 8 mmHg, D

- mannose is not expected to be volatile or undergo volatilization. A log Koc of 10.7 526 suggest s it is a highly mobile compound and will not bind readily to soils or sediments

. I X. E COLOGICAL EFFECTS
Based on the EPI Suite calculations for log BCF of D

- mannose, there is little concern for the bioconcentration of D

- mannose in tissues of organisms. As stated previously in this document, D

- mannose once ingested is expected to be excreted or metabolized by an organism. Most if not all organisms can metabolize D

- mannose as part of their routine metabolic pathway and therefore there is negligible concern for the ecological effect s of D

- mannose. According to the F ood and A gricultural Organization’s (FAO) Aqua culture D evelopment and C oordination P rogramme, m annose is also found in some plant polysaccharides

. W hile mannose is considered8 one of the monosaccharides result ing from carbohydrate digestion in land mammals, there are no similar studies available for f ish http://www.fao.org/docrep/x5738e/x5738e06.htm).

X. D ETERMINATION OF SAFETY

Based on the weight of the evidence , EPA concludes that there is a reasonable certainty that no harm will result to the general population, or to infants and children from aggregate exposure to residues of the D

- mannose when used as an inert ingredient in pesticide formulations applied Preharvest to raw agricultural commodities under 40 CFR 180. 920.

XI. E NVIRONMENTAL JUSTICE 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, HED estimates risks to population subgroups from pesticide exposures that are based on pat terns 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 the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated ri sks 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 spec ialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

XII

. H UMAN STUDIES
This assessment does not rely on any studies in which human subjects were intentionally exposed to a pesticide.

X I II

. I NTERNATIONAL LIMITS

There are no international limits established for D

- mannose

.
IVX

. CONCLUSIONS

.
D

- Mannose is a simple, six carbon sugar that is essential to mammalian metabolic systems. The metabolism of D

- Mannose is thoroughly understood. D

- Mannose occurs naturally in certain9 fruit. It is used therapeutically in the treatment of some human pathol ogical conditions. No toxicological endpoints of concern have been identified for oral, dermal or inhalation exposures to D

- Mannose. There are no concerns for acute, short

- term, intermediate

- term or chronic exposures to D

- Mannose. Therefore the Agency ap proves of the use of D

- Mannose under 40 CFR 180.920 as an inert ingredient which serves as a sequestrant, binder or filler applied pre

harvest to agricultural crops. Approval is without limitation.10 REFERENCES

Alton, G., Hasilik, M., Niehues, R., Panneerselvam, K., Etchison, J.R., Fana, F. and Freez, H. 1998. Direct Utilization of D

- mannose for Mammalian Glycoprotein Biosysthesis. Glycobiology . Vol. 8:3, 285

- 295.
Alton, G., S. Kjaergaard, J. Etchison, F. Skovby and H. Freeze. 1997. Oral Ing estion of Mannose Elevates Blood Mannose Levels: A First Step Toward a Potential Therapy for Carbohydrate

- Deficient Glycoprotein Syndrome Type I. Biochem. Mol. Med. 60:127

- 133.

Bartlett, G.R. 1959. Human R ed C ell G lycointermediates

. J. Biol. Chem. 234: 449.
Bartlett, G.R. 1968. Glucose and Mannose Diphosphate In The Red Blood Cell. Biochem. Biophys. Acta. 156:231.
Eylar, H. 1965. On the Biological Role of Glycoproteins. J. Theoret. Biol. 10: 89.
Gheyas, F., Young, E., Blankenship, S., McFeeters, R. 1996. Dietary Fiber Composition of ‘Starkspur Supreme Delicious’ Apple Fruit as Influenced by Rootstock and Growing Region. Fruit Varieties J. 50:1, 35

- 41.

Herman, R. 1971. D

- mannose Metabolism. I. Amer. J. Clinical Nutrition . 24: 488

- 498.

TOXNET. Hazardous Substances Data Bank (HSDB). On

- line Scientific Search Engine, National Library of Medicine, National Institute of Health. http://www.toxnet.nlm.nih.gov

. http://pathman.smpdb.ca/pathways/SMP00064/pathway?level=2
http://www.fao.org/docrep/x5738e/x5738e06.htm

cc:M.Dow(IIAB) RDI:P.V. Shah
, D. Lieu L. Austin M.I.Dow:S7958:PY1:(703)305

- 5533:IIAB:7505P